4-(condensed cyclicmethyl)-imidazole-2-thiones acting as alpha2 adrenergic agonists

ABSTRACT

Compounds of Formula 1 
     
       
         
         
             
             
         
       
         
         
           
             where the variables have the meaning defined in the specification are agonists of alpha 2  adrenergic receptors. Several compounds of the disclosure are specific or selective to alpha 2B  and/or alpha 2C  adrenergic receptors in preference over alpha 2A  adrenergic receptors. Additionally some of the claimed compounds have no or only minimal cardiovascular and/or sedatory activity. The compounds of Formula 1 are useful as medicaments in mammals, including humans, for treatment of diseases and or alleviations of conditions which are responsive to treatment by agonists of alpha 2  adrenergic receptors. Compounds of Formula 1 which have no significant cardiovascular and/or sedatory activity are useful for treating pain and other conditions with minimal side effects.

This application in a continuation application of U.S. application Ser.No. 11/232,383 filed 20 Sep. 2005 which claims priority to ProvisionalPatent Application 60/612,939, filed 24 Sep. 2004, both of which areincorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to 4-(condensedcyclicmethyl)-imidazole-2-thiones and to their use as agonists,preferably specific or selective agonists of alpha_(2B) and/oralpha_(2C) adrenergic receptors. More specifically the present inventionrelates to the above-noted compounds, to pharmaceutical compositionscontaining these compounds as active ingredient for modulating thealpha₂ adrenergic receptors, and even more specifically for utilizingthese compounds and pharmaceutical compositions to alleviate chronicpain, allodynia, muscle spasticity, diarrhea, neuropathic pain and otherdiseases and conditions.

2. Background Art

Human adrenergic receptors are integral membrane proteins which havebeen classified into two broad classes, the alpha and the betaadrenergic receptors. Both types mediate the action of the peripheralsympathetic nervous system upon binding of catecholamines,norepinephrine and epinephrine.

Norepinephrine is produced by adrenergic nerve endings, whileepinephrine is produced by the adrenal medulla. The binding affinity ofadrenergic receptors for these compounds forms one basis of theclassification: alpha receptors tend to bind norepinephrine morestrongly than epinephrine and much more strongly than the syntheticcompound isoproterenol. The preferred binding affinity of these hormonesis reversed for the beta receptors. In many tissues, the functionalresponses, such as smooth muscle contraction, induced by alpha receptoractivation are opposed to responses induced by beta receptor binding.

Subsequently, the functional distinction between alpha and betareceptors was further highlighted and refined by the pharmacologicalcharacterization of these receptors from various animal and tissuesources. As a result, alpha and beta adrenergic receptors were furthersubdivided into α₁, α₂, β₁, and β₂ subtypes. Functional differencesbetween α₁ and α₂ receptors have been recognized, and compounds whichexhibit selective binding between these two subtypes have beendeveloped. Thus, in published international patent application WO92/0073, the selective ability of the R(+) enantiomer of terazosin toselectively bind to adrenergic receptors of the α₁ subtype was reported.The α₁/α₂ selectivity of this compound was disclosed as beingsignificant because agonist stimulation of the α₂ receptors was said toinhibit secretion of epinephrine and norepinephrine, while antagonism ofthe α₂ receptor was said to increase secretion of these hormones. Thus,the use of non-selective alpha-adrenergic blockers, such asphenoxybenzamine and phentolamine, was said to be limited by their α₂adrenergic receptor mediated induction of increased plasma catecholamineconcentration and the attendant physiological sequelae (increased heartrate and smooth muscle contraction).

For a further general background on the α-adrenergic receptors, thereader's attention is directed to Robert R. Ruffolo, Jr.,α-Adrenoreceptors: Molecular Biology, Biochemistry and Pharmacology,(Progress in Basic and Clinical Pharmacology series, Karger, 1991),wherein the basis of α₁/α₂ subclassification, the molecular biology,signal transduction, agonist structure-activity relationships, receptorfunctions, and therapeutic applications for compounds exhibitingα-adrenergic receptor affinity is explored.

The cloning, sequencing and expression of alpha receptor subtypes fromanimal tissues has led to the subclassification of the α₁adrenoreceptors into α_(1A), α_(1B), and α_(1D). Similarly, the α₂adrenoreceptors have also been classified α_(2A), α_(2B), and α_(2C)receptors. Each α₂ receptor subtype appears to exhibit its ownpharmacological and tissue specificities. Compounds having a degree ofspecificity for one or more of these subtypes may be more specifictherapeutic agents for a given indication than an α₂ receptorpan-agonist (such as the drug clonidine) or a pan-antagonist.

Among other indications, such as the treatment of glaucoma,hypertension, sexual dysfunction, and depression, certain compoundshaving alpha₂ adrenergic receptor agonist activity are known analgesics.However, many compounds having such activity do not provide the activityand specificity desirable when treating disorders modulated by alpha₂adrenoreceptors. For example, many compounds found to be effectiveagents in the treatment of pain are frequently found to have undesirableside effects, such as causing hypotension and sedation at systemicallyeffective doses. There is a need for new drugs that provide relief frompain without causing these undesirable side effects. Additionally, thereis a need for agents which display activity against pain, particularlychronic pain, such as chronic neuropathic and visceral pain.

PCT Publication WO 03/099795 published on Dec. 4, 2003 describes4-(substituted cycloalkylmethyl) imidazole-2-thiones, 4-(substitutedcycloalkenylmethyl) imidazole-2-thiones and related compounds and theiruse as specific or selective agonists of alpha_(2B) and/or alpha_(2C)adrenergic receptors.

PCT Publication WO 02/36162 published on May 10, 2002 discloses somecyloalkenyl-methyl-imidazoles, condensed cyclic-methyl imadazoles and animidazole thione of the following structure

as an alpha_(2B) or alpha_(2C) selective agonist utilized for treatmentof ocular neovascularization.

British Patent 1 499 485, published Feb. 1, 1978 describes certainthiocarbamide derivatives; some of these are said to be useful in thetreatment of conditions such as hypertension, depression or pain.

PCT Publications WO01/00586 published on Jan. 4, 2001 and WO99/28300published on Jun. 10, 1999 describe certain imidazole derivatives actingas agonists of alpha_(2B) and/or alpha_(2C) adrenergic receptors. U.S.Pat. No. 6,313,172 discloses phenylmethyl-thiourea derivatives used fortreatment of pain.

U.S. Pat. No. 4,798,843 describes (phenyl)-imidazole-2-thiones andsubstituted (phenyl)-imidazole-2-thiones.

U.S. Pat. Nos. 6,545,182 and 6,313,172 describephenylmethyl-(2-hydroxy)ethylthioureas which have no significantcardiovascular or sedative effects and are useful for alleviatingchronic pain and allodynia. U.S. Pat. No. 6,534,542 describescycloalkyl, cycloalkenyl, cycloalkylmethyl and cycloalkenylmethyl(2-hydroxy)ethylthioureas and their use as specific or selectiveagonists of alpha_(2B) adrenergic receptors.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of Formula 1

where R₁ is independently H, alkyl of 1 to 4 carbons, CH₂OR₂, or fluorosubstituted alkyl of 1 to 4 carbons;R₂ is independently H, alkyl of 1 to 4 carbons, C(O)R₇, carbocyclic arylor heterocyclic aryl having 1 to 3 heteroatoms independently selectedfrom N, O and S;R₃ is independently selected from the groups consisting of alkyl of 1 to4 carbons, alkenyl of 2 to 4 carbons, alkynyl of 2 to 4 carbons, CH₂OR₂,CH₂N(R₂)₂, CH₂CN, C(O)R₂, C(O)OR₆, SO₃R₆, SO₂N(R₂)₂, CH₂SR₂, F, Cl, Br,I, fluoro substituted alkyl of 1 to 4 carbons, CN, N₃, NO₂, N(R₂)₂, OR₂,SR₂;p is an integer having the values of 0, 1, 2, or 3;R₄ and R₅ together with the carbons to which they are attached jointlyform a carbocyclic or a heterocyclic ring, the heterocyclic ring having5 or 6 atoms in the ring and 1 to 3 heteroatoms independently selectedfrom N, O and S;said carbocyclic or heterocyclic ring jointly formed by R₄ and R₅ beingoptionally substituted with 1 to 7 R₈ groups;R₆ is independently H, alkyl of 1 to 4 carbons, carbocyclic aryl orheterocyclic aryl having 1 to 3 heteroatoms independently selected fromN, O and S;R₇ is H or alkyl of 1 to 4 carbons, andR₈ is independently selected from the groups consisting of alkyl of 1 to4 carbons, alkenyl of 2 to 4 carbons, alkynyl of 2 to 4 carbons, CH₂OR₂,CH₂N(R₂)₂, CH₂CN, C(O)R₂, C(O)OR₆, SO₃R₆, SO₂N(R₂)₂, CH₂SR₂, F, Cl, Br,I, fluoro substituted alkyl of 1 to 4 carbons, CN, N₃, NO₂, N(R₂)₂, OR₂,SR₂ or R₈ is O or S double-bonded to one carbon of said carbocyclic orheterocyclic ring.

In a second aspect the present invention is directed to pharmaceuticalcompositions containing as the active ingredient one or more compoundsof Formula 1, the compositions being utilized as medicaments in mammals,including humans, for treatment of diseases and or alleviations ofconditions which are responsive to treatment by agonists of alpha₂adrenergic receptors. The compositions containing the compounds of theinvention are primarily, but not exclusively, used for alleviation ofchronic pain and/or allodynia. Some of the compounds of the inventionhave the demonstrable advantageous property that they are specific orselective to alpha_(2B) and/or alpha_(2C) adrenergic receptors inpreference over alpha_(2A) adrenergic receptors. In addition some of thealpha 2 agonist compounds have no or only minimal cardiovascular and/orsedatory activity.

DETAILED DESCRIPTION OF THE INVENTION

A general description of the compounds of the invention is provided inthe Summary section of the present application for patent with referenceto Formula 1. It will be readily apparent to those skilled in the artthat some of the compounds depicted in these formulas may exist in trans(E) and cis (Z) isomeric forms. Moreover, some of the compounds of theinvention may contain one or more asymmetric centers, such that thecompounds may exist in enantiomeric as well as in diastereomeric forms.Unless it is specifically noted otherwise, the scope of the presentinvention includes all trans (E) and cis (Z) isomers, enantiomers,diastereomers and racemic mixtures. Some of the compounds of theinvention may form salts with pharmaceutically acceptable acid or base,and such pharmaceutically acceptable salts of the compounds of Formula 1are also within the scope of the invention.

The imidazole-2-thione compounds of the present invention can undergotautomeric transformations and can be depicted by the tautomericformulas shown below. All tautomers of Formula 1 are within the scope ofthe invention.

Generally speaking and referring to Formula 1, in the preferredcompounds of the invention the variable R₁ is H, alkyl of 1 to 4carbons, or CH₂OR₂. Even more preferably one of the R₁ groups is H andthe other is alkyl of 1 to 4 carbons. Still more preferably one of theR₁ groups is methyl and the other is H. Compounds of the invention areequally preferred where both R₁ groups are hydrogen.

The variable p in the presently preferred compounds of the invention iszero (0), meaning that there usually is no R₃ substituent on thearomatic portion of the condensed cyclic moiety in the compounds of theinvention. When there is an R₃ substituent then it is preferably alkylof 1 to 4 carbons, or halogen and p is 1 or 2.

The variables R₄ and R₅ together with the carbons to which they arerespectively attached form a or 6 membered ring and thereby, togetherwith the 6-membered carbocyclic aromatic ring, form an annulated orcondensed cyclic moiety. The 5 or 6 membered ring formed by R₄ and R₅can be carbocyclic or heterocyclic, aromatic or non-aromatic, which areequally preferred. When the annulating ring formed by R₄ and R₅ isheterocyclic then 1 or 2 heteroatoms are preferred in that ring.Presently preferred heteroatoms are nitrogen, oxygen and sulfur.

The optional substituent Rx is not present in the presently preferredcompounds. When the Rx group is present it is preferably, alkyl of 1 to4 carbons, halogen, or O or S double bonded to a ring carbon.

Other compounds have the formula

wherein R₁ is methyl or H, andp is 0 or 1.

Other compounds have the formula

In other words, any of the compounds shown below are possible.

Specifically Contemplated Embodiments

In addition to those embodiments disclosed elsewhere herein. Thefollowing embodiments are specifically contemplated.

Compound Embodiments

One embodiment is a compound of the formula

where R₁ is independently H, alkyl of 1 to 4 carbons, CH₂OR₂, or fluorosubstituted alkyl of 1 to 4 carbons;R₂ is independently H, alkyl of 1 to 4 carbons, C(O)R₇, carbocyclic arylor heterocyclic aryl having 1 to 3 heteroatoms independently selectedfrom N, O and S;R₃ is independently selected from the groups consisting of alkyl of 1 to4 carbons, alkenyl of 2 to 4 carbons, alkynyl of 2 to 4 carbons, CH₂OR₂,CH₂N(R₂)₂, CH₂CN, C(O)R₂, C(O)OR₆, SO₃R₆, SO₂N(R₂)₂, CH₂SR₂, F, Cl, Br,I, fluoro substituted alkyl of 1 to 4 carbons, CN, N₃, NO₂, N(R₂)₂, OR₂,SR₂;p is an integer having the values of 0, 1, 2, or 3;R₄ and R₅ together with the carbons to which they are attached jointlyform a carbocyclic or a heterocyclic ring, the heterocyclic ring having5 or 6 atoms in the ring and 1 to 3 heteroatoms independently selectedfrom N, O and S;said carbocyclic or heterocyclic ring jointly formed by R4 and R5 beingoptionally substituted with 1 to 7 R₈ groups;R₆ is independently H, alkyl of 1 to 4 carbons, carbocyclic aryl orheterocyclic aryl having 1 to 3 heteroatoms independently selected fromN, O and S;R₇ is H or alkyl of 1 to 4 carbons, andR₈ is independently selected from the groups consisting of alkyl of 1 to4 carbons, alkenyl of 2 to 4 carbons, alkynyl of 2 to 4 carbons, CH₂OR₂,CH₂N(R₂)₂, CH₂CN, C(O)R₂, C(O)OR₆, SO₃R₆, SO₂N(R₂)₂, CH₂SR₂, F, Cl, Br,I, fluoro substituted alkyl of 1 to 4 carbons, CN, N₃, NO₂, N(R₂)₂, OR₂,SR₂ or R₈ is O or S double bonded to one carbon of said carbocyclic orheterocyclic ring.

Another embodiment is a compound as described above having the formula

where q is an integer selected from 0, 1, 2, 3, and 4; and R₁, R₃, and pare as described above. Another embodiment is a compound as describeabove having the formula

wherein R₁, R₃, and p are as described above, and q is an integerselected from 0, 1, 2, 3, and 4.

Another embodiment is a compound having the formula

Another embodiment is a compound having the formula

where q is an integer selected from 0, 1, 2, 3, 4, 5 and 6; and R₁, R₃and p are as described above.

Another embodiment is a compound having the formula

where q is an integer selected from 0, 1, 2, 3, 4, 5 and 6; and R₁, R₃and p are as described above.

Another embodiment is a compound having the formula

Another embodiment is a compound having the formula

where q is an integer selected from 0, 1 and 2; and R₁, R₃, and p are asdescribed above.

Another embodiment is a compound having the formula

where q is an integer selected from 0, 1 and 2; and R₁, R₃, and p are asdescribed above.

Another embodiment is a compound having the formula

Another embodiment is a compound having the formula

where q is an integer selected from 0, 1 and 2; and R₁, R₃, and p are asdescribed above.

Another embodiment is a compound having the formula

Another embodiment is a compound having the formula

where q is an integer selected from 0, 1, 2 and 3; and R₁, R₃, and p areas described above.

Another embodiment is a compound having the formula

where q is an integer selected from 0, 1, 2 and 3; and R₁, R₃, and p areas described above.

Another embodiment is a compound having the formula

Another embodiment is a compound having the formula

Another embodiment is a compound having the formula

where q is an integer selected from 0, 1, 2 and 3; and R₁, R₃, and p areas described above.

Another embodiment is a compound having the formula

Another embodiment is a compound having the formula

In another embodiment, the compound above is a substantially puredextrorotatory enantiomer.

In another embodiment, the compound above is a substantially purelevorotatory enantiomer.

Another embodiment is a compound having the formula

where q is an integer selected from 0, 1, 2, 3 and 4; and R₁, R₃, and pare as described above.

Another embodiment is a compound having the formula

where q is an integer selected from 0, 1, 2, 3 and 4; and R₁, R₃, and pare as described above.

Another embodiment is a compound having the formula

Another embodiment is a compound having the formula

Another embodiment is a compound having the formula

where q is an integer selected from 0, 1, 2, 3, and 4; and R₁, R₃, and pare as described above.

Another embodiment is a compound having the formula

where q is an integer selected from 0, 1, 2, 3, and 4; and R₁, R₃, and pare as described above.

Another embodiment is a compound having the formula

Another embodiment is a compound having the formula

where q is an integer selected from 0, 1, 2, 3, and 4; and R₁, R₃, and pare as described above.

Another embodiment is a compound having the formula

Another embodiment is a compound having the formula

Another embodiment is a compound of the formula

where R₁ is independently H, alkyl of 1 to 4 carbons, CH₂OR₂, or fluorosubstituted alkyl of 1 to 4 carbons;R₂ is independently H, alkyl of 1 to 4 carbons, C(O)R₇, carbocyclic arylor heterocyclic aryl having 1 to 3 heteroatoms independently selectedfrom N, O and S;R₃ is independently selected from the groups consisting of alkyl of 1 to4 carbons, alkenyl of 2 to 4 carbons, alkynyl of 2 to 4 carbons, CH₂OR₂,CH₂N(R₂)₂, CH₂CN, C(O)R₂, C(O)OR₆, SO₃R₆, SO₂N(R₂)₂, CH₂SR₂, F, Cl, Br,I, fluoro substituted alkyl of 1 to 4 carbons, CN, N₃, NO₂, N(R₂)₂, OR₂,SR₂;p is an integer having the values of 0, 1, 2, or 3;R₄ and R₅ together with the carbons to which they are attached jointlyform a carbocyclic or a heterocyclic ring, the heterocyclic ring having5 or 6 atoms in the ring and 1 to 3 heteroatoms independently selectedfrom N, O and S;said carbocyclic or heterocyclic ring jointly formed by R4 and R5 beingoptionally substituted with 1 to 7 R₈ groups;R₆ is independently H, alkyl of 1 to 4 carbons, carbocyclic aryl orheterocyclic aryl having 1 to 3 heteroatoms independently selected fromN, O and S;R₇ is alkyl of 1 to 4 carbons, andR₈ is independently selected from the groups consisting of alkyl of 1 to4 carbons, alkenyl of 2 to 4 carbons, alkynyl of 2 to 4 carbons, CH₂OR₂,CH₂N(R₂)₂, CH₂CN, C(O)R₂, C(O)OR₆, SO₃R₆, SO₂N(R₂)₂, CH₂SR₂, F, Cl, Br,I, fluoro substituted alkyl of 1 to 4 carbons, CN, N₃, NO₂, N(R₂)₂, OR₂,SR₂ or R₈ is O or S double bonded to one carbon of said carbocyclic orheterocyclic ring.

Another embodiment is a compound having the formula

wherein R₃, R₄, R₅, and p are as described above.

Another embodiment is a compound having the formula

wherein R₃, R₄, R₅, and p are as described above.

Another embodiment is a compound having the formula

wherein R₃, R₄, R₅, and p are as described above.

Another embodiment is a compound having the formula

wherein R₃, R₄, R₅, and p are as described above.

Another embodiment is a compound having the formula

wherein R₃, R₄, R₅, and p are as described above.

Another embodiment is a compound having the formula

wherein R₃, R₄, R₅, and p are as described above.

Method Embodiments

One embodiment is a method of activating alpha_(2B) or alpha_(2C)adrenergic receptors in a mammal in need of such activation byadministering to the mammal a pharmaceutical composition containing atherapeutically effective dose of a compound, said compound having theformula

where R₁ is independently H, alkyl of 1 to 4 carbons, CH₂OR₂, or fluorosubstituted alkyl of 1 to 4 carbons;R₂ is independently H, alkyl of 1 to 4 carbons, C(O)R₇, carbocyclic arylor heterocyclic aryl having 1 to 3 heteroatoms independently selectedfrom N, O and S;R₃ is independently selected from the groups consisting of alkyl of 1 to4 carbons, alkenyl of 2 to 4 carbons, alkynyl of 2 to 4 carbons, CH₂OR₂,CH₂N(R₂)₂, CH₂CN, C(O)R₂, C(O)OR₆, SO₃R₆, SO₂N(R₂)₂, CH₂SR₂, F, Cl, Br,I, fluoro substituted alkyl of 1 to 4 carbons, CN, N₃, NO₂, N(R₂)₂, OR₂,SR₂;p is an integer having the values of 0, 1, 2, or 3;R₄ and R₅ together with the carbons to which they are attached jointlyform a carbocyclic or a heterocyclic ring, the heterocyclic ring having5 or 6 atoms in the ring and 1 to 3 heteroatoms independently selectedfrom N, O and S;said carbocyclic or heterocyclic ring jointly formed by R4 and R5 beingoptionally substituted with 1 to 7 R₈ groups;R₆ is independently H, alkyl of 1 to 4 carbons, carbocyclic aryl orheterocyclic aryl having 1 to 3 heteroatoms independently selected fromN, O and S;R₇ is H or alkyl of 1 to 4 carbons, andR₈ is independently selected from the groups consisting of alkyl of 1 to4 carbons, alkenyl of 2 to 4 carbons, alkynyl of 2 to 4 carbons, CH₂OR₂,CH₂N(R₂)₂, CH₂CN, C(O)R₂, C(O)OR₆, SO₃R₆, SO₂N(R₂)₂, CH₂SR₂, F, Cl, Br,I, fluoro substituted alkyl of 1 to 4 carbons, CN, N₃, NO₂, N(R₂)₂, OR₂,SR₂ or R₈ is O or S double bonded to one carbon of said carbocyclic orheterocyclic ring.

In another method the pharmaceutical composition is administered to themammal to alleviate pain.

In another method the pharmaceutical composition is administered to themammal to alleviate chronic pain.

In another method the pharmaceutical composition is administered to themammal to alleviate allodynia.

In another method the pharmaceutical composition is administered orally.

In another method the pharmaceutical composition is administeredintraperitonially.

In another method the mammal is administered the composition fortreating a condition selected from the group consisting of chronic pain,visceral pain, neuropathic pain, corneal pain, glaucoma, elevatedintraocular pressure, ischemic neuropathies, neurodegenerative diseases,diarrhea, nasal congestion, muscle spasticity, diuresis, withdrawalsyndromes, neurodegenerative diseases, optic neuropathy, spinalischemia, stroke, memory and cognition deficits, attention deficitdisorder, psychoses, manic disorders, anxiety, depression, hypertension,congestive heart failure, cardiac ischemia, arthritis, spondylitis,gouty arthritis, osteoarthritis, juvenile arthritis, autoimmunediseases, lupus erythematosus, chronic gastrointestinal inflammations,Crohn's disease, gastritis, irritable bowel syndrome (IBS), functionaldyspepsia and ulcerative colitis.

In another method the mammal is administered the composition fortreating glaucoma.

In another method the mammal is administered the composition fortreating neuropathies or neurodegenerative diseases.

In another method the mammal is administered the composition fortreating muscle spasticity.

The presently most preferred compounds of the invention are disclosed bytheir structural formulas in Table 1 together with their activity inassays measuring their ability to act as agonists of alpha_(2A),alpha_(2B) and alpha_(2C) adrenergic receptors.

TABLE 1 Biological Data: Intrinsic Activity Alpha Alpha Alpha Structure2A 2B 2C

0.44 0.94 0.56

0.45 1.38 0.48

0.56 0.97 0.77

0.80 1.03 0.62

NA 1.05 NA

0.48 0.73 0.55

NA 0.90 NA

0.93 1.01 0.75

NA 0.74 NA

0.52 1.21 NA

NA 0.94 NA

0.54 1.15 NA

NA 0.95 NA

NA 0.86 NA

NA 0.89 NA

NA 1.22 0.69

NA 0.98 NA

0.80 1.05 0.41

General Methods for Obtaining the Compounds of the Invention

Reaction Schemes A-E illustrate general methods for obtaining the4-(carbo-bicyclyl)-imidazole-2-thiones and4-(hetero-bicyclyl)-imidazole-2-thiones.

Reaction Scheme A provides a general method for preparing compounds ofFormula 1 where either both R₁ group represent hydrogen, or one R₁ grouprepresent hydrogen and the other an alkyl group or other group definedin Formula 1 for the variable R₁. The remaining variables in ReactionScheme A are defined in the same manner as in connection with Formula 1.An aldehyde or ketone of Formula 2 is the starting material which can beobtained through commercial sources or prepared in accordance with knownprocedures in the chemical scientific and patent literature or bymodifications of known procedures which are readily apparent to thepracticing synthetic organic chemist. The aldehyde or ketone of Formula2 is reacted with a Grignard reagent of4-iodo-1-triphenylmethyl-1H-imidazole to provide the triphenylmethyl(trityl) protected hydroxyimidazole compounds of Formula 3.Deoxygenation of the bridging hydroxyl moiety was accomplished bymethods such as treatment with trifluoroacetic acid (TFA) in triethylsilane (Et₃SiH) or oxidation of the alcohol to a ketone which can bereduced with a Huang-Minlon modification of the Wolff-Kishner reduction,followed by acidic deprotection of the trityl group to produceimidazoles of Formula 4. The imidazoles of Formula 4 are reacted withphenyl chlorothionoformate in the presence of sodium bicarbonate andwater and subsequently treated with a base, such as triethylamine toproduce 4-(carbo-bicyclyl)-imidazole-2-thiones and4-(hetero-bicyclyl)-imidazole-2-thiones of Formula 5. The compounds ofFormula 5 are within the scope of the present invention.

Reaction Scheme B describes another general method for the preparationof 4-(carbo-bicyclyl)-imidazole-2-thiones and4-(hetero-bicyclyl)-imidazole-2-thiones within the scope of the presentinvention where one of the R₁ groups is hydrogen and the other is asdefined in connection with Formula 1. In accordance with this schemecompounds of Formula 3, as prepared in Reaction Scheme A, are oxidizedto the ketone compounds of Formula 6. Addition of a Grignard reagent(R₁MgBR) produces tertiary alcohols of Formula 7. Deoxygenation of thetertiary alcohols is conducted via an elimination/reduction methodology,and removal of the trityl protecting group is accomplished under acidicconditions to deliver imidazole compounds of Formula 8. The imidazolesof Formula 8 are reacted with phenyl chlorothionoformate in the presenceof sodium bicarbonate and water and subsequently treated with a base,such as triethylamine to produce 4-(carbo-bicyclyl)-imidazole-2-thionesand 4-(hetero-bicyclyl)-imidazole-2-thiones of Formula 9.

Reaction Scheme C discloses still another general method for preparingcompounds of the invention where one of the R₁ groups of Formula 1 ishydrogen and the other is as defined in connection with Formula 1. Thisscheme also employs an aldehyde starting material, of Formula 10, whichcan be obtained through commercial sources or prepared in accordancewith known procedures in the chemical scientific and patent literatureor by modifications of known procedures which are readily apparent tothe practicing synthetic organic chemist. The aldehyde of Formula 10 isreacted with tosyl methylisocyanide, (TosMIC) and sodium cyanide andthereafter heated in the presence of excess ammonia to produce theimidazole compounds of Formula 11. The imidazoles of Formula 11 arereacted with phenychlorothionoformate as described above to obtaincompounds of Formula 12.

Reaction Scheme D is yet another general method for preparing compoundsof the invention where one of the R₁ groups of Formula 1 is hydrogen andthe other is as defined in connection with Formula 1. This scheme alsoemploys the aldehyde of Formula 2 as starting material. The aldehyde ofFormula 2 is reacted with a Grignard reagent (R₁MgBr) and the resultingalcohol is converted to the corresponding chloro compound by the actionof thionyl chloride. Nucleophilic displacement of the chloride with thelithium anion of N-(diphenylmethylene)aminoacetonitrile and hydrolysisproduces the amino nitrile compound of Formula 13. A selective reduction(eg. Raney Ni 2800 with amine additives) produces the diamine compoundsof Formula 14. Reaction of the diamines of Formula 15 withthiocarbonyl-diimidazole and protection of the thione withp-methoxybenzylchloride yields compounds of Formula 15. The compounds ofFormula 15 are oxidized with a Swern-type reagent and deprotected underacidic conditions to give compounds of Formula 9.

Reaction Scheme E discloses a general method for preparing compounds ofthe invention where both of the R₁ groups of Formula 1 are hydrogen.Reaction Scheme E is the inverse of Scheme A where the nucleophile(Formula 16) is generated on the general aromatic component. Thisnucleophile (Formula 16) is added to the carbonyl that is appended ontothe protected imidazole compound (Formula 17). Conversion ofintermediates such as Formula 17 is completed by methods found inReaction Scheme A to form compounds of Formula 18.

Example L Method L: Procedure for the preparation of4-Benzo[1,2,5]thiadiazol-4-ylmethyl-1,3-dihydro-imidazole-2-thione(Compound 16) and4-(1-Benzo[1,2,5]thiadiazol-4-yl-ethyl)-1,3-dihydro-imidazole-2-thione(Compound 17) Example L

General Method for the Formation of Intermediate L3:

A suspension of benzo[1,2,5]thiadiazole-4-carboxylic acid (IntermediateL1) (1.8 g, 9.99 mmol) (commercially available from Maybridge) inbenzene (100 mL) was treated with oxalyl chloride (5.1 mL of a 2 MCH₂Cl₂ solution) and DMF (catalytic amount) at rt for 1 h. The solventwas removed under vacuum and re-suspended in benzene. The mixture wasdecanted into a flask and concentrated under vacuum. The acid chlorideintermediate was dissolved in chloroform (10 mL) and added to a solutionof N,O-dimethylhydroxylamine-HCl (1.47 g, 15 mmol) (commerciallyavailable from Aldrich) and triethylamine (4 mL, 30 mmol) in chloroform(90 mL) at 0° C. The mixture was stirred at rt for 2 h. The mixture wassubjected to a standard aqueous work-up. All solvent was removed undervacuum and the residue was purified by chromatography on silica gel with50% EtOAc:hexane to give benzo[1,2,5]thiadiazole-4-carboxylic acidmethoxy-methyl-amide (Intermediate L2) 2 g (90% over two steps).

A mixture of 4-iodo-1-tritylimidazole (commercially available fromSynchem) (6.3 g, 14.4 mmol) in dichloromethane (100 mL) at rt wastreated with ethyl magnesium bromide (4.8 mL, 14.4 mmol, 3M in THF) andallowed to react for 1 h. A solution ofbenzo[1,2,5]thiadiazole-4-carboxylic acid methoxy-methyl-amide(Intermediate L2) (2.0 g, 9.0 mmol) in dichloromethane (50 mL) was addedvia syringe at rt and stirred for 40 m. The residue was isolated in atypical aqueous workup and purified by chromatography on silica gel with30% EtOAc:hexane to givebenzo[1,2,5]thiadiazol-4-yl-(1-trityl-1H-imidazol-4-yl)-methanone(Intermediate L3), 1 g (25%).

Conversion of Intermediate L3 to4-Benzo[1,2,5]thiadiazol-4-ylmethyl-1,3-dihydro-imidazole-2-thione(Compound 16)

A solution ofbenzo[1,2,5]thiadiazol-4-yl-(1-trityl-1H-imidazol-4-yl)-methanone(Intermediate L3) (500 mg, 1.12 mmol) in methylene chloride (2 mL) wastreated with triethylsilane (8 mL), and trifluoroacetic acid (8 mL) atrt for 48 h. This mixture was evaporated under vacuum and quenched witha ˜7M NH₃-MeOH solution. The solvent was exchanged with CH₂Cl₂. Thesolution was concentrated onto silica gel and purified bychromatography, eluting with 3% NH₃-MeOH:CH₂Cl₂ to give4-(1H-imidazol-4-ylmethyl)-benzo[1,2,5]thiadiazole (Intermediate L4).4-(1H-imidazol-4-ylmethyl)-benzo[1,2,5]thiadiazole (Intermediate L4) wassubjected to the appropriate process steps in Method A to produce4-benzo[1,2,5]thiadiazol-4-ylmethyl-1,3-dihydro-imidazole-2-thione(Compound 16).

¹H NMR (300 MHz, DMSO-d⁶ w/TMS): δ 12.01 (s, 1H), 11.76 (s, 1H), 7.98(d, J=9.0 Hz, 1H), 7.69 (t, J=8.7 Hz, 1H), 7.45 (d, J=6.6 Hz, 1H), 6.57(s, 1H), 4.23 (s, 2H).

Conversion of Intermediate L3 to4-Benzo[1,2,5]thiadiazol-4-ylmethyl-1,3-dihydro-imidazole-2-thione(Compound 17)

A solution ofbenzo[1,2,5]thiadiazol-4-yl-(1-trityl-1H-imidazol-4-yl)-methanone(Intermediate L3) (448 mg, 1.0 mmol) in THF (20 mL) at −15° C. wastreated with MeMgBr (0.7 mL, 3M in ether) for ˜1 h. The reaction mixturewas quenched with water and some sodium bicarbonate. The layers wereseparated and dried over MgSO₄, filtered, evaporated and purified bycolumn chromatography on silica gel with 60% EtOAc: hexanes. This gave1-benzo[1,2,5]thiadiazol-4-yl-1-(1-trityl-1H-imidazol-4-yl)-ethanol(Intermediate L5) 130 mg (25%).

1-Benzo[1,2,5]thiadiazol-4-yl-1-(1-trityl-1H-imidazol-4-yl)-ethanol(Intermediate L5) was subjected to the appropriate process steps inMethod A to produce4-(1-benzo[1,2,5]thiadiazol-4-yl-ethyl)-1,3-dihydro-imidazole-2-thione(Compound 17).

¹H NMR (300 MHz, CDCl₃ w/TMS): δ 10.76 (brs, 1H), 10.50 (brs, 1H), 7.90(d, J=8.7 Hz, 1H), 7.53 (t, J=5.1 Hz, 1H), 7.38 (d, J=7.2 Hz, 1H), 6.55(s, 1H), 4.75 (q, J=6.9 Hz, 1H), 1.75 (d, J=7.5 Hz, 2H).

Method M: Procedure for the Preparation of4-[1-(8-methyl-quinolin-7-yl)-ethyl]-1,3-dihydro-imidazole-2-thione(Compound 18) Example M

A mixture of 3-amino-2-methylbenzoic acid (Intermediate M1) (6.06 g,39.6 mmol) (commercially available from Aldrich) and arsenic acid(H₅AS₃O₁₀) 7.43 g (commercially available from VWR/ALFA) in glycerol(5.8 mL, 79.2 mmol), and sulfuric acid (9 mL) was heated to 160° C. for5 h. The mixture was cooled to rt, diluted with water and filteredthrough a bed of diatomaceous earth. The pH was adjusted to pH 6-7 with2 M NaOH. The aqueous layer was exhaustively extracted with CHCl₃:MeOH(3:1). The organic fractions were pooled and evaporated under vacuum togive a solid. This solid was titurated with CHCl₃, and collected on aglass frit. The solid material was washed with hexanes and dried underhigh vacuum to give a pure solid, 8-methylquinoline-7-carboxylic acid(intermediate M2) 3.86 g (51%).

A solution of 8-methylquinoline-7-carboxylic acid (Intermediate M2)(3.86 g, 20.6 mmol) in thionyl chloride (15 mL) was heated to reflux for1 h. The mixture was cooled to rt and concentrated under vacuum. Thematerial was diluted in CH₂Cl₂ and decanted into a clean flask. Themixture was treated with N,O-dimethylhydroxylamine-HCl (3.0 g, 30.1mmol) and triethylamine (10.6 mL, 76 mmol) at 0° C. The mixture wasstirred at rt for several h. After a typical aqueous work-up, theresidue was purified by chromatography on silica gel with 50 to 60%EtOAc:hexane to give N-methoxy-N-8-dimethylquinoline-7-carboxamide(Intermediate M3) 3.91 g (82% over two steps) as in Method L.

N-methoxy-N-8-dimethylquinoline-7-carboxamide (Intermediate M3) (3.91 g,17 mmol) was subjected to the appropriate process steps in Method L toproduce (8-methylquinolin-7-yl)(1-trityl-1H-imidazol-4-yl)methanone(Intermediate M4) 3.59 g (44%).

A solution of(8-methylquinolin-7-yl)(1-trityl-1H-imidazol-4-yl)methanone(Intermediate M4) (3.59 g, 7.49 mmol) in THF (100 mL) at 0° C. wastreated with MeMgBr (5.0 mL, 3M in ether) for 16 h. The reaction mixturewas quenched with NH₄Cl (aq) and extracted with EtOAc. The layers wereseparated and dried over MgSO₄, filtered, evaporated and purified bycolumn chromatography on silica gel with 3 to 4% NH₃-MeOH. The alcoholin CH₂Cl₂ (100 mL) was treated with Et₃N (8.4 mL, 60.3 mmol) and methanesulfonyl chloride (1.75 mL, 22.6 mmol) at 0° C. for 3 h. The mixture wasquenched with water and extracted with CH₂Cl₂. The organic layers werepooled and evaporated to give8-methyl-7-[1-(1-trityl-1H-imidazol-4-yl)vinyl]quinoline (IntermediateM5) 2.14 g (60% over two steps). This material was used in the next stepwithout further purification.

A solution of 8-methyl-7-[1-(1-trityl-1H-imidazol-4-yl)vinyl]quinoline(Intermediate M5) (2.14 g, 4.49 mmol) in TFA (40 mL) was reduced byaction of 10% Pd/C (0.51 g) under H₂ (45-50 psi) for 16 h at rt. Themixture was filtered through celite and the solvent was removed undervacuum. The residue was purified by chromatography on silica gel with24% NH₃-MeOH:CH₂Cl₂ to give7-[1-(1H-imidazol-4-yl)ethyl]-8-methylquinoline (Intermediate M6) 834mg, (79%).

7-[1-(1H-Imidazol-4-yl)ethyl]-8-methylquinoline (Intermediate M6) wassubjected to the appropriate process steps in Method A to produce4-[1-(8-methyl-quinolin-7-yl)-ethyl]-1,3-dihydro-imidazole-2-thione(Compound 18).

¹H NMR (300 MHz, CD₃OD): δ 11.91 (brs, 1H), 11.77 (brs, 1H), 8.92 (dd,J=4.2, 1.8 Hz, 1H), 8.28 (dd, J=8.4, 1.8 Hz, 1H), 7.76 (d, J=8.7 Hz,1H), 7.49 (dd, J=8.1, 4.2 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 6.69 (s, 1H),4.44 (q, J=7.2 Hz, 1H), 2.82 (s, 3H), 1.49 (d, J=7.2 Hz, 3H).

Biological Activity, Modes of Administration

The imidazole-2-thione compounds of the invention are agonists of alpha₂adrenergic receptors. Many compounds of the invention are specific orselective agonists of alpha_(2B) and/or to a lesser extent alpha_(2C)adrenergic receptors, in preference over alpha_(2A) adrenergicreceptors. The specific or selective alpha_(2B) and/or to a lesserextent alpha_(2C) agonist activity of the compounds of the invention isdemonstrated in an assay titled Receptor Selection and Amplificationtechnology (RSAT) assay, which is described in the publication byMessier et. al., 1995, Pharmacol. Toxicol. 76, pp. 308-311 (incorporatedherein by reference) and is also described below. Another referencepertinent to this assay is Conklin et al. (1993) Nature 363:274-6,Receptor Selection and Amplification Technology (RSAT) assay, alsoincorporated herein by reference.

The RSAT assay measures a receptor-mediated loss of contact inhibitionthat results in selective proliferation of receptor-containing cells ina mixed population of confluent cells. The increase in cell number isassessed with an appropriate transfected marker gene such asβ-galactosidase, the activity of which can be easily measured in a96-well format. Receptors that activate the G protein, Gq, elicit thisresponse. Alpha₂ receptors, which normally couple to Gi, activate theRSAT response when coexpressed with a hybrid Gq protein that has a Gireceptor recognition domain, called Gq/i5.

NIH-3T3 cells are plated at a density of 2×10⁶ cells in 15 cm dishes andmaintained in Dulbecco's modified Eagle's medium supplemented with 10%calf serum. One day later, cells are cotransfected by calcium phosphateprecipitation with mammalian expression plasmids encodingp-SV-β-galactosidase (5-10 μg), receptor (1-2 μg) and G protein (1-2μg). 40 μg salmon sperm DNA may also be included in the transfectionmixture. Fresh media is added on the following day and 1-2 days later,cells are harvested and frozen in 50 assay aliquots. Cells are thawedand 100 μl added to 100 μl aliquots of various concentrations of drugsin triplicate in 96-well dishes. Incubations continue 72-96 hr at 37° C.After washing with phosphate-buffered saline, β-galactosidase enzymeactivity is determined by adding 200 μl of the chromogenic substrate(consisting of 3.5 mM o-nitrophenyl-β-D-galactopyranoside and 0.5%nonidet P-40 in phosphate buffered saline), incubating overnight at 30°C. and measuring optical density at 420 nm. The absorbance is a measureof enzyme activity, which depends on cell number and reflects areceptor-mediated cell proliferation. The efficacy or intrinsic activityis calculated as a ratio of the maximal effect of the drug to themaximal effect of a standard full agonist for each receptor subtype.Brimonidine, also called UK14304, the chemical structure of which isshown below, is used as the standard agonist for the alpha_(2A),alpha_(2B) and alpha_(2C) receptors.

Diseases that may be treated with this invention include, but are notlimited to neurodegenerative aspects of the following conditions:MACULOPATHIES/RETINAL DEGENERATION Non-Exudative Age Related MacularDegeneration (ARMD), Exudative Age Related Macular Degeneration (ARMD),Choroidal Neovascularization, Diabetic Retinopathy, Central SerousChorioretinopathy, Cystoid Macular Edema, Diabetic Macular Edema, MyopicRetinal Degeneration,UVEITIS/RETINITIS/CHOROIDITIS/OTHER INFLAMMATORY DISEASES AcuteMultifocal Placoid Pigment Epitheliopathy, Behcet's Disease, BirdshotRetinochoroidopathy, Infectious (Syphilis, Lyme, Tuberculosis,Toxoplasmosis), Intermediate Uveitis (Pars Planitis), MultifocalChoroiditis, Multiple Evanescent White Dot Syndrome (MEWDS), OcularSarcoidosis, Posterior Scleritis, Serpiginous Choroiditis, SubretinalFibrosis and Uveitis Syndrome, Vogt-Koyanagi-Harada Syndrome, PunctateInner Choroidopathy, Acute Posterior Multifocal Placoid PigmentEpitheliopathy, Acute Retinal Pigement Epitheliitis, Acute MacularNeuroretinopathyVASCULAR DISEASES/EXUDATIVE DISEASES Diabetic retinopathy, RetinalArterial Occlusive Disease, Central Retinal Vein Occlusion, DisseminatedIntravascular Coagulopathy, Branch Retinal Vein Occlusion, HypertensiveFundus Changes, Ocular Ischemic Syndrome, Retinal ArterialMicroaneurysms, Coat's Disease, Parafoveal Telangiectasis, Hemi-RetinalVein Occlusion, Papillophlebitis, Central Retinal Artery Occlusion,Branch Retinal Artery Occlusion, Carotid Artery Disease (CAD), FrostedBranch Angiitis, Sickle Cell Retinopathy and other Hemoglobinopathies,Angioid Streaks, Familial Exudative Vitreoretinopathy, Eales DiseaseTRAUMATIC/SURGICAL/ENVIRONMENTAL Sympathetic Ophthalmia, Uveitic RetinalDisease, Retinal Detachment, Trauma, Laser, PDT, Photocoagulation,Hypoperfusion During Surgery, Radiation Retinopathy, Bone MarrowTransplant RetinopathyPROLIFERATIVE DISORDERS Proliferative Vitreal Retinopathy and EpiretinalMembranesINFECTIOUS DISORDERS Ocular Histoplasmosis, Ocular Toxocariasis,Presumed Ocular Histoplasmosis Syndrome (POHS), Endophthalmitis,Toxoplasmosis, Retinal Diseases Associated with HIV Infection, ChoroidalDisease Associate with HIV Infection, Uveitic Disease Associate with HIVInfection, Viral Retinitis, Acute Retinal Necrosis, Progressive OuterRetinal Necrosis, Fungal Retinal Diseases, Ocular Syphilis, OcularTuberculosis, Diffuse Unilateral Subacute Neuroretinitis, MyiasisGENETIC DISORDERS Retinitis Pigmentosa, Systemic Disorders withAssociated Retinal Dystrophies, Congenital Stationary Night Blindness,Cone Dystrophies, Stargardt's Disease And Fundus Flavimaculatus, Best'sDisease, Pattern Dystrophy of the Retinal Pigmented Epithelium, X-LinkedRetinoschisis, Sorsby's Fundus Dystrophy, Benign Concentric Maculopathy,Bietti's Crystalline Dystrophy, pseudoxanthoma elasticumRETINAL TEARS/HOLES Retinal Detachment, Macular Hole, Giant Retinal TearTUMORS Retinal Disease Associated With Tumors, Congenital Hypertrophy OfThe RPE, Posterior Uveal Melanoma, Choroidal Hemangioma, ChoroidalOsteoma, Choroidal Metastasis, Combined Hamartoma of the Retina andRetinal Pigmented Epithelium, Retinoblastoma, Vasoproliferative Tumorsof the Ocular Fundus, Retinal Astrocytoma, Intraocular Lymphoid Tumors.

The results of the RSAT assay with several exemplary compounds of theinvention are disclosed in Table 1 above together with the chemicalformulas of these exemplary compounds. NA stands for “not active” atconcentrations less than 10 micromolar.

Generally speaking alpha₂ agonists, can alleviatesympathetically-sensitized conditions that are typically associated withperiods of stress. These include neurological conditions of: 1)increased sensitivity to stimuli such as intracranial pressure, lightand noise characteristic of migraines and other headaches; 2) theincreased sensitivity to colonic stimuli characteristic of IrritableBowel Syndrome and other GI disorders such as functional dyspepsia; 3)the sensation of itch associated with psoriasis and other dermatologicalconditions; 4) muscle tightness and spasticity; 5) sensitivity tonormally innocuous stimuli such as light touch and spontaneous paincharacteristic of conditions like fibromyalgia; 6) variouscardiovascular disorders involving hypertension, tachycardia, cardiacischemia and peripheral vasoconstriction; 7) metabolic disordersincluding obesity and insulin resistance; 8) behavioral disorders suchas drug and alcohol dependence, obsessive-compulsive disorder,Tourette's syndrome, attention deficit disorder, anxiety and depression;9) altered function of the immune system such as autoimmune diseasesincluding lupus erythematosis and dry eye disorders; 10) chronicinflammatory disorders such as Crohn's disease and gastritis; 11)sweating (hyperhydrosis) and shivering; and 12) sexual dysfunction.

Alpha₂ agonists including alpha_(2B/2C) agonists are also useful in thetreatment of glaucoma, elevated intraocular pressure, neurodegenerativediseases including Alzheimer's, Parkinsons, ALS, schizophrenia, ischemicnerve injury such as stroke or spinal injury, and retinal injury asoccurs in glaucoma, macular degeneration, diabetic retinopathy, retinaldystrophies, Lebers optic neuropathy, other optic neuropathies, opticneuritis often associated with multiple sclerosis, retinal veinocclusions, and following procedures such as photodynamic therapy andLASIX. Also included are chronic pain conditions such as cancer pain,post-operative pain, allodynic pain, neuropathic pain, CRPS orcausalgia, visceral pain.

A compound is considered selective agonist of alpha_(2B) and/oralpha_(2C) adrenergic receptors in preference over alpha_(2A) receptors,if the compound is more active, preferably at least ten (10) times moreactive towards either alpha_(2B) or towards alpha_(2C) receptors thantowards alpha_(2A) receptors. It can be seen from these tables that manycompounds of the invention are specific or selective agonists ofalpha_(2B) and/or alpha_(2C) adrenergic receptors within the formerdefinition, and in fact have no agonist like activity or onlyinsignificant agonist-like activity on alpha_(2A) receptors.

Thus, the imidazole-2-thione compounds of the invention are useful fortreating neurological conditions of conditions and diseases which areresponsive to treatment by alpha₂ and particularly by alpha_(2B) and/oralpha_(2C) adrenergic agonists. Such conditions and diseases include,but are not limited to, pain including chronic pain (which may be,without limitation visceral, inflammatory, referred or neuropathic inorigin) neuropathic pain, corneal pain, glaucoma, reducing elevatedintraocular pressure, ischemic neuropathies and other neurodegenerativediseases, diarrhea, and nasal congestion. Chronic pain may arise as aresult of, or be attendant to, conditions including without limitation:arthritis, (including rheumatoid arthritis), spondylitis, goutyarthritis, osteoarthritis, juvenile arthritis, and autoimmune diseasesincluding without limitation, lupus erythematosus. Visceral pain mayinclude, without limitation, pain caused by cancer or attendant to thetreatment of cancer as, for example, by chemotherapy or radiationtherapy. In addition, the compounds of this invention are useful fortreating muscle spasticity including hyperactive micturition, diuresis,withdrawal syndromes, neurodegenerative diseases including opticneuropathy, spinal ischemia and stroke, memory and cognition deficits,attention deficit disorder, psychoses including manic disorders,anxiety, depression, hypertension, congestive heart failure, cardiacischemia and nasal congestion, chronic gastrointestinal inflammations,Crohn's disease, gastritis, irritable bowel syndrome (IBS), functionaldyspepsia and ulcerative colitis. The activity of the alpha_(2B/2C)specific or selective compounds of the invention is highly advantageousbecause the administration of these compounds to mammals does not resultin sedation or in significant cardiovascular effects (such as changes inblood pressure or heart rate).

The compounds of the invention act and can be used as a highly effectiveanalgesic, particularly in chronic pain models, with minimal undesirableside effects, such as sedation and cardiovascular depression, commonlyseen with other agonists of the alpha₂ receptors.

The compounds of the invention may be administered at pharmaceuticallyeffective dosages. Such dosages are normally the minimum dose necessaryto achieve the desired therapeutic effect; in the treatment of chromicpain, this amount would be roughly that necessary to reduce thediscomfort caused by the pain to tolerable levels. Generally, such doseswill be in the range 1-1000 mg/day; more preferably in the range 10 to500 mg/day. However, the actual amount of the compound to beadministered in any given case will be determined by a physician takinginto account the relevant circumstances, such as the severity of thepain, the age and weight of the patient, the patient's general physicalcondition, the cause of the pain, and the route of administration.

The compounds are useful in the treatment of pain in a mammal;particularly a human being. Preferably, the patient will be given thecompound orally in any acceptable form, such as a tablet, liquid,capsule, powder and the like. However, other routes may be desirable ornecessary, particularly if the patient suffers from nausea. Such otherroutes may include, without exception, transdemmal, parenteral,subcutaneous, intranasal, intrathecal, intramuscular, intravenous, andintrarectal modes of delivery. Additionally, the formulations may bedesigned to delay release of the active compound over a given period oftime, or to carefully control the amount of drug released at a giventime during the course of therapy.

Another aspect of the invention is drawn to therapeutic compositionscomprising the compounds of Formula 1 and pharmaceutically acceptablesalts of these compounds and a pharmaceutically acceptable excipient.Such an excipient may be a carrier or a diluent; this is usually mixedwith the active compound, or permitted to dilute or enclose the activecompound. If a diluent, the carrier may be solid, semi-solid, or liquidmaterial that acts as a excipient or vehicle for the active compound.The formulations may also include wetting agents, emulsifying agents,preserving agents, sweetening agents, and/or flavoring agents. If usedin an ophthalmic or infusion format, the formulation will usuallycontain one or more salts to influence the osmotic pressure of theformulation.

In another aspect, the invention is directed to methods for thetreatment of pain, particularly chronic pain, through the administrationof one or more compounds of Formula 1 or pharmaceutically acceptablesalts thereof to a mammal in need thereof. As indicated above, thecompound will usually be formulated in a form consistent with thedesired mode of delivery.

It is known that chronic pain (such as pain from cancer, arthritis, andmany neuropathic injuries) and acute pain (such as that pain produced byan immediate mechanical stimulus, such as tissue section, pinch, prick,or crush) are distinct neurological phenomena mediated to a large degreeeither by different nerve fibers and neuroreceptors or by arearrangement or alteration of the function of these nerves upon chronicstimulation. Sensation of acute pain is transmitted quite quickly,primarily by afferent nerve fibers termed C fibers, which normally havea high threshold for mechanical, thermal, and chemical stimulation.While the mechanisms of chronic pain are not completely understood,acute tissue injury can give rise within minutes or hours after theinitial stimulation to secondary symptoms, including a regionalreduction in the magnitude of the stimulus necessary to elicit a painresponse. This phenomenon, which typically occurs in a region emanatingfrom (but larger than) the site of the original stimulus, is termedhyperalgesia. The secondary response can give rise to profoundlyenhanced sensitivity to mechanical or thermal stimulus.

The A afferent fibers (Aβ and A* fibers) can be stimulated at a lowerthreshold than C fibers, and appear to be involved in the sensation ofchronic pain. For example, under normal conditions, low thresholdstimulation of these fibers (such as a light brush or tickling) is notpainful. However, under certain conditions such as those following nerveinjury or in the herpes virus-mediated condition known as shingles theapplication of even such a light touch or the brush of clothing can bevery painful. This condition is termed allodynia and appears to bemediated at least in part by Aβ afferent nerves. C fibers may also beinvolved in the sensation of chronic pain, but if so it appears clearthat persistent firing of the neurons over time brings about some sortof change which now results in the sensation of chronic pain.

By “acute pain” is meant immediate, usually high threshold, pain broughtabout by injury such as a cut, crush, burn, or by chemical stimulationsuch as that experienced upon exposure to capsaicin, the activeingredient in chili peppers.

By “chronic pain” is meant pain other than acute pain, such as, withoutlimitation, neuropathic pain, visceral pain (including that broughtabout by Crohn's disease and irritable bowel syndrome (IBS)), andreferred pain.

The following in vivo assays can be employed to demonstrate thebiological activity of the compounds of the invention.

Sedative Activity

To test sedation, six male Sprague-Dawley rats are given up to 3 mg/kgof the test compound in a saline or DMSO vehicle by intraperitonealinjection (i.p.). Sedation is graded 30 minutes following administrationof the drug by monitoring locomotor skills as follows.

The Sprague-Dawley rats are weighed and 1 ml/kg body weight of anappropriate concentration (ie. 3 mg/ml for a final dose of 3 mg/kg) drugsolution is injected intraperitoneally. Typically the test compound isformulated in approximately 10 to 50% DMSO. The results are compared tocontrols that are injected with 1 ml/kg saline or 10 to 50% DMSO. Ratactivity is then determined 30 minutes after injection of the drugsolution. Rats are placed in a dark covered chamber and a digicomanalyzer (Omnitech Electronic) quantitates their exploratory behaviorfor a five-minute period. The machine records each time the ratinterrupts an array of 32 photoelectric beams in the X and Yorientation. Representative Compounds 7 and 15 of the invention weretested in this assay intraperitoneally and up to a dose of 1 mg/kg, andwere found to have no sedative effect. The results in this test withother compounds of the invention are also expected to show that thecompounds of the invention have no significant sedatory activity.

Effects on Cardiovascular System

To test the effect of the compounds on the cardiovascular system,typically six cynomolgus monkeys are given 500 μg/kg of the testcompound by intravenous injection (i.v.) Or 3 mg/kg by oral gavage. Theeffects of the compound on the animals' blood pressure and heart rate ismeasured at time intervals from 30 minutes to six hours followingadministration of the drug. The peak change from a baseline measurementtaken 30 minutes before drug administration is recorded using a bloodpressure cuff modified for use on monkeys.

Specifically and typically the monkeys are weighed (approximately 4 kg)and an appropriate volume (0.1 ml/kg) of a 5 mg/ml solution of the testcompound formulated in 10 to 50% DMSO is injected into the cephalic veinin the animals' arm. Cardiovascular measurements are made with a BP 100Sautomated sphygmomanometer (Nippon Colin, Japan) at 0.5, 1, 2, 4 and 6hours.

The results of this test are expected to show that the compounds of theinvention have no or only minimal detectable effect on thecardiovascular system.

Alleviation of Acute Pain

Models to measure sensitivity to acute pain have typically involved theacute application of thermal stimuli; such a stimulus causes aprogrammed escape mechanism to remove the affected area from thestimulus. The proper stimulus is thought to involve the activation ofhigh threshold thermoreceptors and C fiber dorsal root ganglion neuronsthat transmit the pain signal to the spinal cord.

The escape response may be “wired” to occur solely through spinalneurons, which receive the afferent input from the stimulated nervereceptors and cause the “escape” neuromuscular response, or may beprocessed supraspinally—that is, at the level of the brain. A commonlyused method to measure nociceptive reflexes involves quantification ofthe withdrawal or licking of the rodent paw following thermalexcitation. See Dirig, D. M. et al., J. Neurosci. Methods 76:183-191(1997) and Hargreaves, K. et al., Pain 32:77-88 (1988), herebyincorporated by reference herein.

In a variation of this latter model, male Sprague-Dawley rats are testedby being placed on a commercially available thermal stimulus deviceconstructed as described in Hargreaves et al. This device consists of abox containing a glass plate. The nociceptive stimulus is provided by afocused projection bulb that is movable, permitting the stimulus to beapplied to the heel of one or both hindpaws of the test animal. A timeris actuated with the light source, and the response latency (defined asthe time period between application of the stimulus and an abruptwithdrawal of the hindpaw) is registered by use of a photodiode motionsensor array that turns off the timer and light. Stimulus strength canbe controlled by current regulation to the light source. Heating isautomatically terminated after 20 seconds to prevent tissue damage.

Typically four test animals per group are weighed (approximately 0.3 kg)and injected intraperitonealy (i.p.) with 1 ml/kg of the test compoundformulated in approximately 10 to 50% dimethylsulfoxide (DMSO) vehicle.Animals typically receive a 0.1 mg/kg and a 1 mg/kg dose of the threecompounds. Rats are acclimated to the test chamber for about 15 minutesprior to testing. The paw withdrawal latency is measured at 30, 60 and120 minutes after drug administration. The right and left paws aretested 1 minute apart, and the response latencies for each paw areaveraged. Stimulus intensity is sufficient to provide a temperature of45-50 degrees centigrade to each rat hindpaw.

Alleviation of Chronic Pain

A model in accordance with Kim and Chung 1992, Pain 150, pp 355-363(Chung model), for chronic pain (in particular peripheral neuropathy)involves the surgical ligation of the L5 (and optionally the L6) spinalnerves on one side in experimental animals. Rats recovering from thesurgery gain weight and display a level of general activity similar tothat of normal rats. However, these rats develop abnormalities of thefoot, wherein the hindpaw is moderately everted and the toes are heldtogether. More importantly, the hindpaw on the side affected by thesurgery appears to become sensitive to pain from low-thresholdmechanical stimuli, such as that producing a faint sensation of touch ina human, within about 1 week following surgery. This sensitivity tonormally non-painful touch is called “tactile allodynia” and lasts forat least two months. The response includes lifting the affected hindpawto escape from the stimulus, licking the paw and holding it in the airfor many seconds. None of these responses is normally seen in thecontrol group.

Rats are anesthetized before surgery. The surgical site is shaved andprepared either with betadine or Novocaine. Incision is made from thethoracic vertebra XIII down toward the sacrum. Muscle tissue isseparated from the spinal vertebra (left side) at the L4-S2 levels. TheL6 vertebra is located and the transverse process is carefully removedwith a small rongeur to expose the L4-L6 spinal nerves. The L5 and L6spinal nerves are isolated and tightly ligated with 6-0 silk thread. Thesame procedure is done on the right side as a control, except noligation of the spinal nerves is performed.

A complete hemostasis is confirmed, then the wounds are sutured. A smallamount of antibiotic ointment is applied to the incised area, and therat is transferred to the recovery plastic cage under a regulatedheat-temperature lamp. On the day of the experiment, at least seven daysafter the surgery, typically six rats per test group are administeredthe test drugs by intraperitoneal (i.p.) injection or oral gavage. Fori.p. injection, the compounds are formulated in d H₂O and given in avolume of 1 ml/kg body weight using an 18-gauge, 3 inch gavage needlethat is slowly inserted through the esophagus into the stomach.

Tactile allodynia is measured prior to and 30 minutes after drugadministration using von Frey hairs that are a series of fine hairs withincremental differences in stiffness. Rats are placed in a plastic cagewith a wire mesh bottom and allowed to acclimate for approximately 30minutes. The von Frey hairs are applied perpendicularly through the meshto the mid-plantar region of the rats' hindpaw with sufficient force tocause slight buckling and held for 6-8 seconds. The applied force hasbeen calculated to range from 0.41 to 15.1 grams. If the paw is sharplywithdrawn, it is considered a positive response. A normal animal willnot respond to stimuli in this range, but a surgically ligated paw willbe withdrawn in response to a 1-2 gram hair. The 50% paw withdrawalthreshold is determined using the method of Dixon, W. J., Ann. Rev.Pharmacol. Toxicol. 20:441-462 (1980) hereby incorporated by reference.The post-drug threshold is compared to the pre-drug threshold and thepercent reversal of tactile sensitivity is calculated based on a normalthreshold of 15.1 grams.

TABLE 2 Activity of the Compounds of the Invention in the Chung Model ofNeuropathic Pain (% Pain Reversal ± SEM) Dose and Route ofAdministration of Compound 7 10 μg/kg 30 μg/kg 300 μg/kg Compd. i.p.i.p. i.p. 7 2.9 ± 0.7 65.8 ± 6.1 77.7 ± 7.2 Dose and Route ofAdministration of Compounds 7 and 15 3 μg/kg 10 μg/kg 30 μg/kg 100 μg/kgCompd. p.o. p.o. p.o. p.o.. 7 77.0 ± 5.1 15 58.0 ± 5.3 78.0 ± 4.6 82.0 ±6.2 81.0 ± 8.1All measurements 30 min following drug administration.p value <0.001 compared to pretreatment values.

The results shown in Table 2 illustrate that these compounds of theinvention significantly alleviate allodynic pain, and based on thesetest and/or on the compounds ability to activate alpha_(2B) and/oralpha_(2C) adrenergic receptors in preference over alpha_(2A) adrenergicreceptors, the compounds of the invention are expected to be useful asanalgesics to alleviate allodynia and chronic pain.

The Mouse Sulprostone Model is an alternative model in which chronicpain, allodynia can be induced in mice through intrathecal treatment ofthe animals with 200 ng sulprostone (prostaglandin E2 receptor agonist)in 50% DMSO and in volume of 5 μl. In this model, the pain response tostroking the flank with a paint brush is scored 8 times over a 35 minuteperiod starting 15 minutes following final administration ofsulprostone. Minami et al., 57 Pain 217-223 (1994), hereby incorporatedby reference. Sulprostone treatment alone elicits a score of 12-13 on a16-point scale.

In variants of this model, allodynia can be induced usingintraperitoneal injection of 300 μg/kg sulprostone or 30 μg/kgphenylephrine. Alternatively allodynia can be induced using intrathecalinjection of 100 ng N-methyl-D-aspirate (NMDA) or 30 ng phenylephrine(PE) formulated in dH₂O in a volume of e.g. 5 microliters.

In either model, the compounds are formulated in dH₂O and given in avolume of 1 ml/kg body weight for intraperitoneal (IP) dosing.

Specific Embodiments, Experimental Example A Method A: Procedure for thepreparation of4-(2,3-dihydro-benzo[1,4]dioxin-5-ylmethyl)-1,3-dihydro-imidazole-2-thione(Compound 1)

A solution of 2,3-dihydro-1,4-benzodioxin-5-ylmethanol (Intermediate A1)(commercially available from Aldrich) (3 g, 18.1 mmol) in THF (100 mL)was treated with manganese(IV) oxide, activated (commercially availablefrom Aldrich): MnO₂ (10 g, 115 mmol) at rt. The mixture was heated to35° C. for 2 h and 60° C. for 4 h followed by 18 h at room temperature(rt). The mixture was filtered through celite and the solvent wasremoved under vacuum. The residue was purified by chromatography onsilica gel with 20% EtOAc: hexanes to give2,3-dihydro-benzo[1,4]dioxine-5-carbaldehyde (Intermediate A2) 2.6 g(88%).

A mixture of 4-iodo-1-tritylimidazole (commercially available) (8.64 g,19.8 mmol) in dichloromethane (100 mL) at −10° C. was treated with ethylmagnesium bromide (6.3 mL, 19 mmol, 3M in THF) and allowed to react for45 m. A solution of 2,3-dihydro-benzo[1,4]dioxine-5-carbaldehyde(Intermediate A2) (2.6 g, 15.9 mmol) in dichloromethane was added viasyringe at −10° C. and stirred for 45 m. The mixture was quenched withwater (50 mL) and a sat. solution of ammonium chloride (50 mL). Theresidue was isolated in a typical aqueous workup and purified bychromatography on silica gel with 3 to 5% NH₃-MeOH:CH₂Cl₂ to give(2,3-dihydro-benzo[1,4]dioxin-5-yl)-(1-trityl-1H-imidazol-4-yl)-methanol(Intermediate A3) as a solid, 2.9 g (40%).

A solution of(2,3-dihydro-benzo[1,4]dioxin-5-yl)-(1-trityl-1H-imidazol-4-yl)-methanol(Intermediate A3) (1 g, 2.11 mmol) in dichloromethane (30 mL) wasreacted with TFA: trifluoroacetic acid (5.3 mL, 68 mmol)) andtriethylsilane (TES) (2.8 mL, 17 mmol) at rt for 24 h. The mixture wasevaporated under reduced pressure and quenched with solid NaHCO₃. Thismaterial was subjected to an aqueous work-up and the residue waspurified by chromatography on silica gel with 5% NH₃-MeOH:CH₂Cl₂ toyield 5-(2,3-dihydro-benzo[1,4]dioxin-5-ylmethyl)-1H-imidazole(Intermediate A4) 330 mg (72%).

A mixture of 5-(2,3-dihydro-benzo[1,4]dioxin-5-ylmethyl)-1H-imidazole(Intermediate A4) (260 mg, 1.2 mmol) in THF (10 mL) and water (10 mL)was treated with NaHCO₃ (1 g, 12 mmol) and phenylchlorothionoformate(0.42 mL, 3.13 mmol) for 3 h at rt. The mixture was diluted with diethylether (35 mL) and water (10 mL). The aqueous layer was removed andextracted with ether (2×10 mL). The organic layers were combined, driedover MgSO₄, filtered and concentrated under vacuum. The residue wastreated with triethylamine (1 mL) in methanol (9 mL) at rt for 16 h. Thesolvent was removed and the product was isolated and purified either bytituration with CH₂Cl₂: hexane or by chromatography on SiO₂ with EtOAcor 3% MeOH:CH₂Cl₂. This gave4-(2,3-dihydro-benzo[1,4]dioxin-5-ylmethyl)-1,3-dihydro-imidazole-2-thione(Compound-1) 150 mg (50%).

¹H NMR (300 MHz, DMSO-d⁶ w/TMS): δ 11.9 (brs, 1H), 11.7 (s, 1H),6.76-6.65 (m, 3H), 6.41 (s, 1H), 4.28-4.21 (m, 4H), 3.61 (s, 2H).

Example B Method B Procedure for the preparation of4-[1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethyl]-1,3-dihydro-imidazole-2-thione(Compound-2)

2,3-Dihydro-benzo[1,4]dioxine-5-carbaldehyde (Intermediate A2) wasoxidized by manganese dioxide (in accordance with the applicable step ofMethod A) to give(2,3-dihydro-benzo[1,4]dioxin-5-yl)-(1-trityl-1H-imidazol-4-yl)-methanone(Intermediate B1) (83%).

A solution of(2,3-dihydro-benzo[1,4]dioxin-5-yl)-(1-trityl-1H-imidazol-4-yl)-methanone(Intermediate B1) (0.91 g, 1.93 mmol) in THF (80 mL) at −10° C. wastreated with MeMgBr (2.6 mL, 7.68 mmol of a 3M solution in Et₂O) for 45m. The mixture was quenched with a sat. solution of NH₄Cl and water. Thelayers were separated and the organic layer dried over MgSO₄. Thesuspension was filtered and evaporated to dryness. The material waspurified by chromatography on SiO₂ with 50% EtOAc in CHCl₃ to give1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-1-(1-trityl-1H-imidazol-4-yl)-ethanolas a foam 0.95 g (98%).

A solution of1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-1-(1-trityl-1H-imidazol-4-yl)-ethanol(0.95 g) in dichloromethane (10 mL) was treated with trifluoroaceticacid (6 mL) and triethylsilane (4 mL) at rt for 24 h. The reactionmixture was quenched with solid NaHCO₃ and subjected to an aqueouswork-up. The residue was purified by chromatography on silica gel with4% NH₃-MeOH: CH₂Cl₂ to give a mixture of two products:4-[1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethyl]-1H-imidazole and4-[1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-vinyl]-1H-imidazole.

A mixture of4-[1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethyl]-1H-imidazole and4-[1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-vinyl]-1H-imidazole (350 mg) inEtOH (35 mL) was reduced by the action of 10% Pd/C (100 mg) under H₂ at35 psi for 12 h at rt. The mixture was filtered through Celite and freedof solvent under reduced pressure. The residue was purified bychromatography on silica gel with 5% NH₃-MeOH: CH₂Cl₂ to give4-[1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethyl]-1H-imidazole(Intermediate-B2) as a solid, 280 mg (80%).

4-[1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethyl]-1H-imidazole(Intermediate-B2) (250 mg, 1.09 mmol) was subjected to the applicablesteps of Method A to produce4-[1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethyl]-1,3-dihydro-imidazole-2-thione(Compound-2) as a white solid, 80 mg (35%).

¹H NMR (300 MHz, DMSO-d⁶ w/TMS): δ 11.9 (brs, 1H), 11.7 (s, 1H),6.77-6.58 (m, 3H), 6.46 (s, 1H), 4.28-4.18 (m, 5H), 1.38 (d, J=6.9 Hz,3H).

Example B-1 Compound-3

Use of 2,3-(methylenedioxy)benzaldehyde (commercially available fromAldrich) in Method B produced4-(1-benzo[1,3]dioxol-4-yl-ethyl)-1,3-dihydro-imidazole-2-thione(Compound-3).

¹H NMR (300 MHz, methanol-d⁴): δ 6.79-6.60 (m, 3H), 6.54 (d, J=1.2 Hz,1H), 5.92 (s, 2H), 4.09 (q, J=6.6 Hz, 1H), 1.52 (d, 7.2 Hz, 3H).

Example C Method C: Procedure for the preparation of4-(1-quinolin-8-yl-ethyl)-1,3-dihydro-imidazole-2-thione (Compound 4)

Quinoline-8-carbaldehyde (commercially available from Lancaster) wassubjected to the applicable process steps in Method B to produce1-quinolin-8-yl-1-(1-trityl-1H-imidazol-4-yl)-ethanol (Intermediate C1).

1-Quinolin-8-yl-1-(1-trityl-1H-imidazol-4-yl)-ethanol (Intermediate C1)and p-toluenesulfonic acid catalyst in toluene was heated to reflux in aDean-Stark apparatus for 18 h. The mixture was cooled to rt and freed ofsolvent. The residue was dissolved in 70% acetic acid:water and heatedto 100° C. for 1 h. The reaction mixture was cooled to rt and basifiedwith 2 M NaOH and extracted with chloroform: isopropyl alcohol (3:1).The organic layers were pooled, dried over MgSO₄, filtered andconcentrated onto silica gel. The product was eluted from a column ofsilica gel with 4% NH₃-MeOH: CH₂Cl₂ to give8-[1-(1H-imidazol-4-yl)-vinyl]-quinoline.

The vinyl compound, 8-[1-(1H-imidazol-4-yl)-vinyl]-quinoline (0.23 g) intrifluoroacetic acid: TFA (15 mL) was reduced by the action of 10% Pd/C(58 mg) under 50 psi of hydrogen for 18 h at rt. The mixture wasfiltered through Celite and basified with NH₃-MeOH. The solvent wasremoved under vacuum. The residue was purified by chromatography onsilica gel with 4% NH₃-MeOH: CH₂Cl₂ to give8-[1-(1H-imidazol-4-yl)-ethyl]-quinoline (Intermediate C2) 0.2 g.

8-[1-(1H-Imidazol-4-yl)-ethyl]-quinoline (Intermediate C2) was subjectedto the appropriate process steps in Method A to produce4-(1-quinolin-8-yl-ethyl)-1,3-dihydro-imidazole-2-thione (Compound-4).

¹H NMR (300 MHz, methanol-d⁴): δ 8.93-8.91 (m, 1H), 8.33-8.30 (m, 1H),7.83-7.80 (m, 1H), 7.56-7.48 (m, 3H), 6.65 (s, 1H), 5.40 (q, J=9 Hz,1H), 1.64 (d, J=6 Hz, 3H).

Example D Method D: Procedure for the preparation of4-benzo[1,3]dioxol-5-ylmethyl-1,3-dihydro-imidazole-2-thione(Compound-5)

A solution of 3,4-(methylenedioxy)phenylacetic acid (Intermediate D1)(commercially available from Aldrich) (2 g, 11 mmol) in diethyl ether(40 mL) and THF (60 mL) was treated with lithium aluminum hydride:LiAlH₄ (24 mL, 1 M in ether) at rt for 16 h. Rochelle's salt solutionwas added to quench the reaction mixture. The aqueous layer wasextracted with ether (3×100 mL). The combined organic fractions weredried over MgSO₄, filtered and evaporated to give 1.8 g of2-benzo[1,3]dioxol-5-yl-ethanol (Intermediate D2) that was sufficientlypure to be used in the next synthetic step.

A solution of 2-benzo[1,3]dioxol-5-yl-ethanol (Intermediate D2) (1 g,6.0 mmol) in dichloromethane (40 mL) was treated with the Dess-Martinperiodinane (commercially available from Lancaster) (2.65 g, 6.25 mmol)at rt for 2 h. Silica gel was added to the mixture and the solvent wasremoved under vacuum. The solids were placed onto a column of silica geland the product was eluted with a mixture of ether: hexanes to givebenzo[1,3]dioxol-5-yl-acetaldehyde (Intermediate D3) 0.75 g.

This preparation of Intermediate D4 followed the procedure by Horne, D.A.; Yakushijin, K.; Büchi, G. Heterocycles, 1994, 39, 139 (“Büchiprotocol”) incorporated herein by reference. A solution ofbenzo[1,3]dioxol-5-yl-acetaldehyde (Intermediate D3) (0.75 g, 4.57 mmol)in EtOH (10 mL) was treated with tosylmethyl isocyanide (TosMIC) (0.87g, 4.45 mmol) and NaCN (˜15 mg, cat.). This mixture was allowed to stirat rt for 20 m. The solvent was removed in vacuo and the residue wasdissolved in ˜7M NH₃ in MeOH (45 mL) and transferred to a resealabletube. This mixture was heated to at 90-100° C. for 12 h. The mixture wasconcentrated and purified by chromatography on SiO₂ with 5% MeOH (sat.w/NH₃):CH₂Cl₂ to give 4-benzo[1,3]dioxol-5-ylmethyl-1H-imidazole(Intermediate D4) 0.4 g (43%) as an amber oil.

A solution of 4-benzo[1,3]dioxol-5-ylmethyl-1H-imidazole (IntermediateD4) (0.24 g, 1.18 mmol) in THF (4 mL) and water (4 mL) was treated withNaHCO₃ (1 g, 11.9 mmol) at rt for 10 m. Phenyl chlorothionoformate (0.42mL, 3.1 mmol) was added and stirring was continued for 3 h. The mixturewas diluted with water (10 mL) and extracted with ether (3×15 mL). Theorganic portions were combined, dried over MgSO₄, filtered and freed ofsolvent. The residue was dissolved in MeOH (8 mL) and treated with NEt₃(1 mL) for 16 h. The solvent was removed under vacuum and the productwas washed on a glass frit with 50% CH₂Cl₂:hexanes to give a white solid(˜36%) 4-benzo[1,3]dioxol-5-ylmethyl-1,3-dihydro-imidazole-2-thione(Compound 5)

¹H NMR (300 MHz, DMSO-d⁶ w/TMS): δ 11.9 (brs, 1H), 11.6 (br s, 1H),6.84-6.82 (m, 2H), 6.72-6.71 (m, 1H), 6.52 (s, 1H), 5.95 (s, 2H), 3.58(s, 2H).

Example D-1

Use of 1-naphthalene ethanol (commercially available from Aldrich) inMethod D produced 4-naphthalen-1-ylmethyl-1,3-dihydro-imidazole-2-thione(Compound-6).

¹H NMR (500 MHz, DMSO-d⁶ w/TMS): δ 12.02 (brs, 1H), 11.70 (s, 1H), 8.10(d, J=4.8 Hz, 1H), 7.94 (d, J=4.2 Hz, 1H), 7.83 (d, J=5.1 Hz, 1H),7.54-7.52 (m, 1H), 7.46 (t, J=4.2 Hz, 1H), 7.38 (d, J=4.2 Hz, 1H), 6.48(s, 1H), 4.17 (s, 2H).

Example E Method E: Procedure for the Preparation of4-(1-quinolin-5-yl-ethyl)-1,3-dihydro-imidazole-2-thione (Compound 7)

A solution of quinoline-5-carbaldehyde (available from Lancaster or RareChemicals GmbH) (4.65 g, 29.5 mmol) in THF (250 mL) was treated withMeMgI (11.8 mL, 35.4 mmol of a 3M solution in ether) in a dropwisefashion at 0° C. After 2 h the mixture was quenched with water, dilutedwith ethyl acetate, filtered through celite and separated into twolayers. The aqueous layer was extracted with ethyl acetate/hexane. Theorganic fractions were pooled, dried over MgSO₄, filtered, andevaporated to dryness. The alcohol, 1-quinolin-5-yl-ethanol was usedwithout further purification, 5.0 g (97%).

The alcohol, 1-quinolin-5-yl-ethanol (5.0 g, 28.9 mmol) in chloroformwas treated with a dropwise addition of thionyl chloride (5.26 mL, 72.1mmol) at rt. After 1 h the mixture was cooled to 0° C. and carefullyquenched with a sat. solution of NaHCO₃ followed by 2M NaOH until the pHwas >8. The aqueous layer was extracted with chloroform and the organicfractions were combined, dried over MgSO₄, filtered, and freed ofsolvent. The residue was purified by chromatography on SiO₂ eluting with30% ethyl acetate:hexane. The product, 5-(1-chloro-ethyl)-quinoline(Intermediate E1) was obtained as a clear oil, 4.22 g (76%).

A solution of N-(diphenylmethylene)aminoacetonitrile (5.84 g, 26.0 mmol,commercially available from Aldrich) in THF (20 mL) andhexamethylphosphoramide (HMPA) (5.43 mL, 31 mmol) at −78° C. was reactedwith lithium diisopropylamide (LDA) (15.4 mL of a 2M soln inheptane/THF/ethylbenzene) (commercially available from Aldrich). After 1h, 5-(1-chloro-ethyl)-quinoline (Intermediate E1) (4.15 g, 21.7 mmol) inTHF (15 mL) was introduced by dropwise addition. The mixture was kept at−78° C. for 5 m before removal of the cold bath. After 5 m, the mixturewas quenched with cold water and extracted with ethyl acetate (3×). Theorganic solution was dried over MgSO₄, filtered and concentrated to give2-(benzhydrylidene-amino)-3-quinolin-5-yl-butyronitrile that was used inthe next step without further purification.

2-(Benzhydrylidene-amino)-3-quinolin-5-yl-butyronitrile (8.36 g, 22.3mmol) in dioxane (90 mL) was hydrolyzed with 1M HCl (90 mL) and thesolution was stirred at rt for 16 h. The dioxane was removed undervacuum and the mixture was made basic with 2 M NaOH. The aqueoussolution was extracted with chloroform:isopropanol (3:1). The organicextracts were pooled, dried over MgSO₄, filtered and evaporated to leavean oil. The oily residue was purified by chromatography on SiO₂, elutingwith ethyl acetate and 5% methanol:ethyl acetate to give2-amino-3-quinolin-5-yl-butyronitrile (Intermediate-E2) as a yellowsolid 3.61 g (77%).

In a Parr bottle, a mixture of 2-amino-3-quinolin-5-yl-butyronitrile(Intermediate-E2) (5.38 g, 25.4 mmol) in MeOH (100 mL) and ethylenediamine (3.2 mL, 47.8 mmol) was reacted with Raney 2800 nickel (18.9 g)and bubbled with ammonia gas for 10 m. The Parr bottle was pressurizedwith hydrogen at 50 psi and shaken on a Parr apparatus for 2.5 h at rt.The mixture was filtered through celite, washed with MeOH (3×) andevaporated to leave a residue. This material was placed onto a columnand eluted with a gradient of 1% to 5% sat. NH₃-MeOH:CH₂Cl₂ to give3-quinolin-5-yl-butane-1,2-diamine (Intermediate E3) 3.9 g (71%).

3-Quinolin-5-yl-butane-1,2-diamine (Intermediate E3) (1.8 g, 8.35 mmol)in CH₂Cl₂ (20 mL) was treated with a solution of1,1′-thiocarbonyldiimidazole (1.52 g, 8.54 mmol) in CH₂Cl₂ (40 mL) at 0°C. for 1 h. The mixture was diluted with chloroform (40 mL) and water(60 mL). The aqueous layer was extracted with chloroform (3×30 mL) andCH₂Cl₂ (6×30 mL). The organic solution was dried over MgSO₄, filteredand evaporated to give a residue. The material was purified bychromatography on SiO₂ with 3% NH₃-MeOH:CH₂Cl₂ to give4-(1-quinolin-5-yl-ethyl)-imidazolidine-2-thione (Intermediate E4) 2 g(93%).

A mixture of 4-(1-quinolin-5-yl-ethyl)-imidazolidine-2-thione(Intermediate E4) (4.0 g, 15.5 mmol) in ethanol (120 mL) was treatedwith p-methoxybenzylchloride (4.22 mL, 27 mmol). The solution was heatedin an oil bath (bath temp. 100° C.) for 1 h. The solvent was removedunder vacuum and replaced with 10% NaOH (160 mL). The aqueous mixturewas extracted with CH₂Cl₂ (2×100 mL) and chloroform (2×100 mL). Theorganic solution was dried over MgSO₄, filtered, evaporated and purifiedby chromatography on SiO₂ eluting with 2 to 4% NH₃-MeOH:CH₂Cl₂. Theproduct was5-{1-[2-(4-methoxy-benzylsulfanyl)-4,5-dihydro-3H-imidazol-4-yl]-ethyl}-quinoline(Intermediate E5) 4.16 g (71%).

A Swern-type reagent was formed in standard fashion: oxalyl chloride(9.15 mL as a 2M soln. in CH₂Cl₂) in CH₂Cl₂ (23 mL) was cooled to −78°C. and treated with a solution of DMSO (2.85 mL, 36.8 mmol) in CH₂Cl₂(23 mL) for 30 m. To this solution was added5-{1-[2-(4-methoxy-benzylsulfanyl)-4,5-dihydro-3H-imidazol-4-yl]-ethyl}-quinoline(Intermediate E5) (4.7 g, 12.4 mmol) in CH₂Cl₂ (30 mL) and stirringcontinued for 45 m at −78° C. Triethylamine (9 mL) was added at −78° C.and warmed to rt for 40 m. The reaction mixture was diluted with brineand CH₂Cl₂. The aqueous layer was extracted with ethyl acetate. Theorganic solution was dried over MgSO₄, filtered and evaporated todryness. Chromatography on SiO₂ with 80 to 100% ethyl acetate:hexanesyielded5-{1-[2-(4-methoxy-benzylsulfanyl)-3H-imidazol-4-yl]-ethyl}-quinoline(Intermediate E6) 3.45 g (74%).

5-{1-[2-(4-Methoxy-benzylsulfanyl)-3H-imidazol-4-yl]-ethyl}-quinoline(Intermediate E6) (3 g, 8.0 mmol) and trifluoroacetic acid (100 mL) in aresealable tube was heated to 115° C. for 1 h 20 m. The mixture wascooled to rt and TFA removed under vacuum. The residual acid wasquenched with NH₃-MeOH. The residue was evaporated and resolvated with3:1 chloroform:isopropanol (500 mL). The organic solution was washedwith water (3×40 mL) and brine (1×30 mL). The solution was dried overMgSO₄, filtered, and evaporated to leave a solid. This material waspurified on a short column of silica gel by gradient elution with 3 to9% NH₃-MeOH: CH₂Cl₂ to give4-(1-quinolin-5-yl-ethyl)-1,3-dihydro-imidazole-2-thione (Compound 7)1.44 g (71%).

¹H NMR (300 MHz, methanol-d⁴): δ 8.85 (dd, J=4.2, 1.5 Hz, 1H), 8.67 (d,J=8.4 Hz, 1H), 7.95 (d, J=9.0 Hz, 1H), 7.73 (dd, J=8.4, 7.2 Hz, 1H),7.58 (dd, J=8.7, 4.5 Hz, 1H), 7.42 (d, J=6.6 Hz, 1H), 6.62 (s, 1H),4.80-4.85 (m, 1H), 1.67 (d, J=7.2 Hz, 3H).

Continuation of Method E: Procedure for the Preparative Chiral HPLCSeparation of Racemic (Compound 7) to provide(−)-4-(1-quinolin-5-yl-ethyl)-1,3-dihydro-imidazole-2-thione (Compound14) and (+)-4-(1-quinolin-5-yl-ethyl)-1,3-dihydro-imidazole-2-thione(Compound 15)

The racemate, 4-(1-quinolin-5-yl-ethyl)-1,3-dihydro-imidazole-2-thione(Compound 7) (˜1.9 g) was separated by preparative Chiral HPLC with aCHIRALCEL-ODH column (available from Chiral Technologies, Inc.) eluentCO₂/MeOH: 80/20 at rt, 2 mL/min flow rate and 280 nm. The first elutingfraction was obtained after 8.6 m to give 0.61 g of(+)-4-(1-quinolin-5-yl-ethyl)-1,3-dihydro-imidazole-2-thione (Compound14) [α]₂₀ ^(D)+101.5° (c=1.16 in DMSO). The second eluting fraction wasobtained after 10.9 min to give 0.67 g of(−)-4-(1-quinolin-5-yl-ethyl)-1,3-dihydro-imidazole-2-thione (Compound15) [∀]₂₀ ^(D) −110° (c=0.54 in DMSO).

Example F Method F: Procedure for the preparation of4-quinolin-8-ylmethyl-1,3-dihydro-imidazole-2-thione (Compound-8)

Quinoline-8-carbaldehyde (commercially available from Lancaster) wassubjected to the applicable process steps in Method A to produce(1H-imidazol-4-yl)-quinolin-8-yl-methanone (Intermediate F1).

1(1H-imidazol-4-yl)-quinolin-8-yl-methanone (Intermediate F1) (0.85 g,3.81 mmol) and KOH (0.86 g, 15.3 mmol) in ethylene glycol (15 mL) wastreated with hydrazine hydrate (˜1.5 mL) and heated to 120° C. for 4-6 hfollowed by heating to 180° C. for 6 h. The mixture was cooled to rt,diluted with brine, and extracted with chloroform:isopropanol (3:1). Theorganic solution was concentrated under vacuum. The residue was purifiedby chromatography on silica gel, eluting with 3% NH₃-MeOH: CH₂Cl₂ togive 8-(1H-imidazol-4-ylmethyl)-quinoline (Intermediate F2) as an oil.

8-(1H-imidazol-4-ylmethyl)-quinoline (Intermediate F2) was subjected tothe appropriate process steps in Method A to produce4-quinolin-8-ylmethyl-1,3-dihydro-imidazole-2-thione (Compound-8)

¹H NMR (300 MHz, methanol-d⁴): δ 8.92 (dd, J=4.2, 1.8 Hz, 1H), 8.31 (dd,J=8.1, 1.5 Hz, 1H), 7.83 (dd, J=7.8, 1.2 Hz, 1H), 7.61-7.50 (series ofm, 3H), 6.48 (s, 1H), 4.42 (s, 2H).

Example G Method G: Procedure for the preparation of4-quinolin-5-ylmethyl-1,3-dihydro-imidazole-2-thione (Compound 9)

Quinoline-5-carbaldehyde (commercially available from Lancaster) wassubjected to the applicable synthetic steps in Method A to producequinolin-5-yl-(1-trityl-1H-imidazol-4-yl)-methanone (Intermediate G1).

Quinolin-5-yl-(1-trityl-1H-imidazol-4-yl)-methanone (Intermediate G1) inacetic acid:water (˜2:1) was heated to 100° C. for 1 h. The mixture wasbasified with 1 M NaOH and extracted (6×) with CHCl₃: iPrOH (3:1). Theorganic solution was dried over MgSO₄, filtered, and concentrated ontosilica gel. The material was eluted from a column of silica with 5%NH₃-MeOH: CH₂Cl₂ to give (1H-imidazol-4-yl)-quinolin-5-yl-methanone(Intermediate G2).

(1H-Imidazol-4-yl)-quinolin-5-yl-methanone (Intermediate G2) wassubjected to the appropriate process steps in Method F to produce4-quinolin-5-ylmethyl-1,3-dihydro-imidazole-2-thione (Compound-9)

¹H NMR (300 MHz, DMSO-d⁶): δ 12.02 (brs, 1H), 11.71 (s, 1H), 8.88 (d,J=3.0 Hz, 1H), 8.55 (d, J=8.4 Hz, 1H), 7.91 (d, J=8.1 Hz, 1H), 7.69(J=8.1 Hz, 1H), 7.56-7.46 (series of m, 2H), 6.50 (s, 1H), 4.18 (s, 2H).

Example H Method H: Procedure for the Preparation of4-(1-quinolin-8-yl-ethyl)-1,3-dihydro-imidazole-2-thione (Compound-10)

A mixture of 4-iodo-1-tritylimidazole (commercially available) (4.5 g,10.3 mmol) in dichloromethane (50 mL) at 22° C. was treated with ethylmagnesium bromide (3.48 mL, 10.4 mmol, 3M in ether) and allowed to reactfor 1 h. Anhydrous CeCl₃ (3.3 g, 13.4 mmol) was added and the mixturewas stirred for 30 m. A solution of 1-acetonaphthone (commerciallyavailable from Aldrich) (2.6 g, 15.9 mmol) in dichloromethane was addedvia syringe at 22° C. and stirred for 16 h. The mixture was quenchedwith a sat. solution of ammonium chloride (50 mL). The residue wasisolated in a typical aqueous workup and purified by chromatography onsilica gel with 50% EtOAc:hexane to give1-naphthalen-1-yl-1-(1-trityl-1H-imidazol-4-yl)-ethanol (IntermediateH1) as a solid, 2.44 g (49%).

1-Naphthalen-1-yl-1-(1-trityl-1H-imidazol-4-yl)-ethanol (IntermediateH1) in acetic acid:water (˜2:1) was heated to 100° C. for 1 h. Themixture was basified with 1 M NaOH and extracted (6×) with CHCl₃: iPrOH(3:1). The organic solution was dried over MgSO₄, filtered, andconcentrated onto silica gel. The material was eluted from a column ofsilica with 5% NH₃-MeOH: CH₂Cl₂ to give4-(1-naphthalen-1-yl-vinyl)-1H-imidazole.

4-(1-Naphthalen-1-yl-vinyl)-1H-imidazole was subjected to theappropriate process steps in Method C to produce4-(1-naphthalen-1-yl-ethyl)-1,3-dihydro-imidazole-2-thione(Compound-10).

¹H NMR (300 MHz, DMSO-d⁶ w/TMS): δ 11.90 (brs, 1H), 11.71 (brs, 1H),8.16 (d, 7.8 Hz), 7.94-7.79 (m, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.57-7.43(m, 3H), 7.29 (dd, J=7.2, 1 Hz, 1H), 6.58 (s, 1H), 4.75 (q, J=7.2 Hz,1H), 1.56 (d, J=6.9 Hz).

Example I Method I: Procedure for the preparation of4-naphthalen-2-ylmethyl-1,3-dihydro-imidazole-2-thione (Compound-11)

A solution of N,N-dimethyl imidazole-1-sulfonamide (commerciallyavailable from Aldrich) (2.0 g, 11.4 mmol) in THF (50 mL) at −78° C. wastreated with nBuLi (4.6 mL of a 2.5 M soln) for 1 h. Solidtert-butyl-dimethylsilanyl chloride (TBSCl) (1.72 g, 11.4 mmol) in THF(10 mL) was added at rt for 16 h. The mixture was cooled to −20° C. andtreated with nBuLi (4.6 mL of a 2.5 M soln) for 1 h. 2-Naphthaldehyde(1.78 g, 11.4 mmol) in THF (10 mL) was added and the mixture was stirredfor 3 h at rt. The mixture was washed with brine and dried over Na₂SO₄.The solvent was removed under vacuum and the residue was purified bychromatography on silical gel with 25% EtOAc:hexane to give2-(tert-butyl-dimethyl-silanyl)-4-(hydroxy-naphthalen-2-yl-methyl)-imidazole-1-sulfonicacid dimethylamide (Intermediate-I1) 2.6 g (50%).

2-(tert-Butyl-dimethyl-silanyl)-4-(hydroxy-naphthalen-2-yl-methyl)-imidazole-1-sulfonicacid dimethylamide (Intermediate-I1) (2.6 g, 5.4 mmol) in THF (30 mL)was treated with tetrabutylammonium fluoride (TBAF) (5.8 mL of a IMsoln) at rt for 1 h. The reaction mixture was subjected to an aqueouswork-up and the product was purified by chromatography on silica gelwith 66% EtOAc:hexane to give4-(hydroxy-naphthalen-2-yl-methyl)-imidazole-1-sulfonic aciddimethylamide as a white solid, 1.54 g (80%).4-(Hydroxy-naphthalen-2-yl-methyl)-imidazole-1-sulfonic aciddimethylamide (1.0 g, 3.0 mmol) was deoxygenated with TES in TFAaccording to the applicable procedures outlined in Method A to give4-naphthalen-2-yl-methyl-imidazole-1-sulfonic acid dimethylamide(Intermediate-I2) as a white solid 0.55 g, (58%).

A solution of 4-naphthalen-2-ylmethyl-imidazole-1-sulfonic aciddimethylamide (0.55 g, 1.7 mmol) in 1.5 M HCl (15 mL) was heated toreflux for 3 h. The mixture was cooled to rt and basified with NaOHsolution. The mixture was extracted with ethyl acetate (2×) and theorganic solution was dried over Nα₂SO₄, filtered and evaporated to give4-naphthalen-2-yl-methyl-1H-imidazole (Intermediate-I3) as a white solid0.31 g (87%).

4-Naphthalen-2-yl-methyl-1H-imidazole (Intermediate-I3) was subjected tothe appropriate process steps in Method A to produce4-naphthalen-2-ylmethyl-1,3-dihydro-imidazole-2-thione (Compound 11).

¹H NMR (500 MHz, DMSO-d⁶ w/TMS): δ 12.02 (s, 1H), 11.74 (s, 1H),7.89-7.84 (m, 3H), 7.74 (s, 1H), 7.50-7.40 (m, 3H), 6.62 (s, 1H), 3.87(s, 2H).

Example J Method J: Procedure for the preparation of4-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)ethyl]-1,3-dihydro-imidazole-2-thione(Compound 12)

1,4-Benzodioxan-6-yl methyl ketone (commercially available from Aldrich)(1.56 g, 8.73 mmol a 10% excess) was subjected to the appropriateprocess steps in Method I to produce4-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-vinyl]-imidazole-1-sulfonicacid dimethylamide (Intermediate-J1) as a white solid 0.64 g (24%).

4-[1-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-vinyl]-imidazole-1-sulfonicacid dimethylamide (Intermediate-J1) (0.25 g, 0.75 mmol) in EtOH (10 mL)was reduced with 10% Pd/C catalyst (25 mg) under 40 psi of hydrogen atrt for 2.5 h. The mixture was filtered through Celite. The solution wasconcentrated and the residue was dissolved in 1.5 M HCl (10 mL) andheated to reflux for 3 h. The mixture was cooled to rt and basified withsat solution of NaHCO₃. The mixture was extracted with ethyl acetate(2×) and the organic solution was dried over Na₂SO₄, filtered andevaporated to give4-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-1H-imidazole(Intermediate-J2) as a tan solid 0.14 g (87%).

4-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-1H-imidazole(Intermediate-J2) was subjected to the appropriate process steps inMethod A to produce4-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-1,3-dihydro-imidazole-2-thione(Compound 12).

¹H NMR (300 MHz, CDCl₃ w/TMS): δ 10.9 (brs, 1H), 10.2 (brs, 1H),6.78-6.68 (m, 3H), 6.40 (s, 1H), 4.24-4.22 (m, 5H), 1.50 (d, J=7.2 Hz,3H).

Example K Method K: Procedure for the Preparation of4-thiochroman-6-ylmethyl-1,3-dihydro-imidazole-2-thione (Compound-13)

General Method for the formation of Intermediate K1: Dimethyl formamideand N,N-dimethyl imidazole-1-sulfonamide (commercially available fromAldrich) was subjected to the appropriate process steps in Method I toform 2-(tert-butyl-dimethyl-silanyl)-5-formyl-imidazole-1-sulfonic aciddimethylamide (Intermediate K1).

6-Bromo-thiochroman-4-one (Intermediate-K2) (prepared according to theprocedures found in Johnson, A. T. et al Bioorg Med. Chem. 1999, 7,1321. incorporated herein by reference) (1.11 g, 4.6 mmol) in MeOH (46mL) was treated with sodium borohydride (0.14 g, 4.6 mmol) at 0° C. for30 m. The mixture was subjected to a standard aqueous work-up and thealcohol, 6-bromo-thiochroman-4-ol, was used in the next step withoutfurther purification. 6-Bromo-thiochroman-4-ol (˜4.5 mmol) in DMF (20mL) was treated with imidazole (0.31 g) and TBSCl (0.69 g) at rt for 16h. After an aqueous work-up the residue was purified by chromatographyon silica gel with 10% EtOAc: hexanes to afford(6-bromo-thiochroman-4-yl-oxy)-tert-butyl-dimethyl-silane(Intermediate-K3) as a yellow oil, 1.06 g.

A solution of (6-bromo-thiochroman-4-yl-oxy)-tert-butyl-dimethyl-silane(Intermediate-K3) (2.74 g, 7.64 mmol) in THF (30 mL) was treated withnBuLi (3.1 mL of a 2.5 M soln) at −78° C. for 30 m. A solution of2-(tert-butyl-dimethyl-silanyl)-5-formyl-imidazole-1-sulfonic aciddimethylamide (see the General Method above, Intermediate K1) (2.42 g,7.63 mmol) in THF (10 mL) was added via cannula. After 15 m, thereaction mixture was allowed to warm to rt for 16 h. The mixture wasquenched with water, washed with brine and dried over Na₂SO₄. Thesolvent was removed and the residue was purified by chromatography onsilica gel with 20% EtOAc:hexane to afford2-(tert-butyl-dimethyl-silanyl)-5-{[4-(tert-butyl-dimethyl-silanyloxy)-thiochroman-6-yl]-hydroxy-methyl}-imidazole-1-sulfonicacid dimethylamide (Intermediate K4) as an oil, 4.12 g.

2-(tert-Butyl-dimethyl-silanyl)-5-{[4-(tert-butyl-dimethyl-silanyloxy)-thiochroman-6-yl]-hydroxy-methyl}-imidazole-1-sulfonicacid dimethylamide (Intermediate K4) was subjected to the appropriateprocess steps in Method I and Method A to produce4-thiochroman-6-ylmethyl-1,3-dihydro-imidazole-2-thione (Compound 13).

¹H NMR (500 MHz, DMSO-d⁶ w/TMS): δ 11.93 (brs, 1H), 11.68 (s, 1H), 6.97(d, J=7.5 Hz, 1H), 6.93 (s, 1H), 6.83 (d, J=7.5 Hz, 1H), 6.55 (s, 1H),3.56 (s, 2H), 3.00-2.96 (m, 2H), 2.72-2.70 (m, 2H) 1.98-1.96 (m, 2H).

1. A compound of the formula

where R₁ is independently H, alkyl of 1 to 4 carbons, CH₂OR₂, or fluorosubstituted alkyl of 1 to 4 carbons; R₂ is independently H, alkyl of 1to 4 carbons, C(O)R₇, carbocyclic aryl or heterocyclic aryl having 1 to3 heteroatoms independently selected from N, O and S; R₃ isindependently selected from the groups consisting of alkyl of 1 to 4carbons, alkenyl of 2 to 4 carbons, alkynyl of 2 to 4 carbons, CH₂OR₂,CH₂N(R₂)₂CH₂CN, C(O)R₂, C(O)OR₆, SO₃R₆, SO₂N(R₂)₂CH₂SR₂, F, Cl, Br, I,fluoro substituted alkyl of 1 to 4 carbons, CN, N₃, NO₂, N(R₂)₂, OR₂,SR₂; p is an integer having the values of 0, 1, 2, or 3; R₄ and R₅together with the carbons to which they are attached jointly form acarbocyclic or a heterocyclic ring, the heterocyclic ring having 5 or 6atoms in the ring and 1 to 3 heteroatoms independently selected from N,O and S; said carbocyclic or heterocyclic ring jointly formed by R₄ andR₅ being optionally substituted with 1 to 7 R₈ groups; R₆ isindependently H, alkyl of 1 to 4 carbons, carbocyclic aryl orheterocyclic aryl having 1 to 3 heteroatoms independently selected fromN, O and S; R₇ is H or alkyl of 1 to 4 carbons, and R₈ is independentlyselected from the groups consisting of alkyl of 1 to 4 carbons, alkenylof 2 to 4 carbons, alkynyl of 2 to 4 carbons, CH₂OR₂, CH₂N(R₂)₂, CH₂CN,C(O)R₂, C(O)R₆, SO₃R₆, SO₂N(R₂)₂, CH₂SR₂, F, Cl, Br, I, fluorosubstituted alkyl of 1 to 4 carbons, CN, N₃, NO₂, N(R₂)₂, OR₂, SR₂ or R₈is O or S double bonded to one carbon of said carbocyclic orheterocyclic ring.
 2. The compound according to claim 1 which is usedfor the treatment of a condition selected from the group consisting ofhypertension, depression, glaucoma, elevated intraocular pressure,ischemic neuropathies, optic neuropathy, corneal pain, headache pain,migraine, cancer pain, back pain, muscle pain, fibromyalgia, painassociated with diabetic neuropathy, the treatment of diabeticretinopathy, stroke, drug dependence, withdrawal symptoms, obsessivecompulsive disorder, obesity, insulin resistance, diarrhea, nasalcongestions, spasticity, and attention deficit disorder.
 3. The compoundaccording to claim 1 wherein the compound is administered to a humanpatient in the range of about 1-1000 mg/day.
 4. The compound accordingto claim 3 wherein the compound is administered to a human patient inthe range of about 10 to about 500 mg/day.
 5. The compound according toclaim 3 wherein the compound may be administered to a patient by one ofthe routes selected from the group consisting of transdermal,parenteral, subcutaneous, intranasal, intrathecal, intramuscular, andintravenous.